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Lymphatics in Cardiovascular Disease

Originally publishedhttps://doi.org/10.1161/ATVBAHA.120.314735Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:e275–e283

    The lymphatic system is a unidirectional network that is universally distributed in almost all vascularized organs and tissues. They serve crucial roles in regulating tissue fluid homeostasis, absorption of dietary lipid, and immune surveillance.1 Compared with their blood vascular counterpart, the research on lymphatics is lagging for years, partly due to lack of specific lymphatic markers. The rapid evolution of genetic tools and imaging technology in recent years, however, has accelerated the discovery of novel functions that the lymphatic system plays, such as reverse cholesterol transport, wound healing, and tissue regeneration. Dysregulation of lymphatic function causes a variety of diseases, including tissue swelling, inflammation, tumor metastases, metabolic disturbance, neurodegeneration, and cardiovascular disorders. Recently, many publications in Arteriosclerosis, Thrombosis, and Vascular Biology and other journals2–5 have demonstrated the progresses in research into the impact of lymphatics in cardiovascular diseases, especially involving in the development and pathological status. In the present article, we provide an overview of the anatomic basis and embryonic development of lymphatic system and discuss recent work highlighting the lymphatics in the pathogenesis of cardiovascular disease, including atherosclerosis, myocardial infarction, hypertension, and heart transplantation. Targeting the lymphatic system may serve as a promising strategy for the treatment of cardiovascular diseases.

    Anatomy and Physiology of Lymphatics

    The lymphatic system is a drainage network composed of capillaries, precollector and collector vessels, and lymph nodes. The blind-ended lymphatic capillaries are tiny, thin-wall vessels of <100 μm in diameter, comprising of a single layer of oak-leaf shaped lymphatic endothelial cells. As characterized by the discontinuous button-like junctions, discontinuous basement membrane, and anchoring filaments that keep the lumen open, they are highly permeable for absorbing interstitial fluids and solutes, as well as trafficking immune cell transcellularly. Lymphatic capillaries highly express the molecular marker Lyve1 (lymphatic vessel endothelial hyaluronan receptor 1) and chemokines like CCL21 (CC-ligand 21)6 to recruit dendritic cells.7 Once taken up into lymphatics capillaries, lymph is transferred through precollecting and larger collecting lymphatic vessels. In contrast to lymphatic capillaries, collecting vessels are equipped with zipper-like junctions, continuous basement membrane, intraluminal valves, and coverage of smooth muscle cells, all facilitating the transportation process. After passing through the lymph nodes chained along the collecting vessels, where appropriate immune response is initiated, the lymph is ultimately drained to the thoracic duct and transported back to the blood circulatory system at the lymph-venous connection via subclavian vein.

    The lymphatic vessels are distributed in almost all vascularized organs, including the previously unappreciated organs like heart and vessel. Early studies in various animal models have also found the presence of lymphatic vessels in the artery. In rabbit, for example, a small number of lymphatic vessels were detected in the adventitia and surrounding areas but not in the intima or media of the carotid and thoracic aorta.8 In human internal carotid artery specimen, Lyve1+ and Pdpn (podoplanin)+ lymphatics are present in arterial adventitia, and their numbers correlated with the severity of intimal thickness.9 As will be discussed later in detail, adventitial lymphatic vessels were increasingly found to be related to vascular pathologies, such as balloon-induced neointimal hyperplasia and atherosclerosis.10 In the mammalian heart, by using the dye injection technique, the existence of cardiac lymphatic vessels was also found in the cardiac walls, including the myocardium, subepicardium, and subendocardium, as well as in the atrioventricular and semilunar valves.11–13 The lymphatic vessels of the heart are mainly located in the epicardium and endocardium with few in the myocardium. Cardiac lymphatic capillaries form complicated networks with ramifications and anastomosis13 and can be found in subepicardium, myocardium, and subendocardium. The direction of lymphatic drainage is from subendocardial lymphatics toward the subepicardial lymphatics, eventually leading to the mediastinal lymph nodes. The lymphatic capillaries converged to form collector vessels in the subepicardial space. The collector vessels merged into single or multiple lymphatic trunks then entered the mediastinal lymphatic vessels including the right lymphatic duct and the thoracic duct, and finally converged into the subclavian vein.11 The walls of the lymphatic collector vessels in the human heart were thin and contained only a few smooth muscle cells. Myocardial contraction is thought to be the driving force of lymphatic transport.14 Therefore, when the cardiac contractility decreases or the heart rate increases, the cardiac lymphatic transport capacity decreases.

    Generally, the principal function of lymphatic system is to collect extravasated fluid, immune cells, and macromolecules in the periphery and transport them back to the blood circulation.15 It plays an integral role in maintaining tissue fluid balance, immune surveillance, and lipid homeostasis. The total plasma volume in the human body exudates from the blood vascular system about every nine hours, and most of the fluid is returned to the blood circulation through the lymphatic system.16 Lymphatic drainage in the mice with deficiency of lymphatics is insufficient, resulting in tissue edema, which is called lymphedema. Thus, the lymphatic system is vital for tissue fluid homeostasis. Lymphatic system also participates in immune surveillance. It plays a major role in trafficking of immune cells and antigen to the lymph nodes, where the immune response is initiated. Lymphatic endothelial cells attract activated antigen-presenting cells and leukocytes that express corresponding receptors by expressing several chemokines, such as CCL19 (CC-ligand 19), CCL21, and CCL27 (CC-ligand 27). In addition, there is an important relationship between lymphatic system and lipid homeostasis.17 Intestinal lymphatics absorb dietary lipids packed into chylomicrons and transport them to the blood, which is essential for the uptake of fat-soluble vitamins.17,18 Interestingly, there is a close anatomic relationship between lymph nodes and adipose tissue, that is, lymph nodes are always surrounded by adipose tissue. Several studies have shown that the adipose tissue around the lymph nodes can provide energy for local immune responses. Recent studies have uncovered lymphatics participate in wound repair and tissue regeneration, including postinjury scar resolution and cardiac regeneration in zebrafish, and are essential for regulating hair follicle stem cells niche for skin regeneration.19 Therefore, lymphatics play a vital role in the homeostasis of the organs in physiology.

    Development of Lymphatic System

    The embryonic origin of the lymphatic vasculature has been historically debated for a century. As proposed by anatomist Florence Sabin, the centrifugal model suggested that lymphatics arose from embryonic veins and expands by sprouting and growing.20 In contrast, Huntington and McClure21 formulated the centripetal model, arguing that lymphatics vessels develop from mesenchymal lymphagioblasts and connect to veins. With recent novel technologies using genetic perturbations and living imaging, these two models are now gradually reconciled, agreeing on dual origins of venous- and nonvenous-derived lymphatics. In fact, it is now postulated that the fate of endothelial cells in different vessel beds is imprinted and specified as early as cells transition through the paraxial mesoderm.22

    The formation of venous-derived primitive lymphatic vessels begins at embryonic day (E) 9.5 in mouse when a subpopulation of Prox1 (prospero homeobox 1)-expressing progenitors in the cardinal vein and intersomitic vessels become primed and committed to lymphatic lineage.23 Lymphatic endothelial cell specification requires Prox1 transactivation by Sox18 (SRY-box 18) and COUP transcription factor (also known as Nr2f2), and the Prox1-VEGFR (vascular endothelial growth factor receptor)-3 feed-forward loop.24 At E10.5, the budding cells from the cardinal veins began expressing Pdpn and migrate away to coalesce to assemble the bilateral chains of lymphatic sacs. The expansion of lymphatic vessels involved budding, proliferation, sprouting and migration of lymphatic endothelial cells, a multistep process depends on VEGFR-3 signaling, its coreceptor neuropilin 2 and calcium-binding epidermal growth factor domains 1-aided proteolytic activation of VEGF-C by the a disintegrin and metalloprotease with thrombospondin motifs-3 metalloprotease.25,26 A number of other molecules have also been recently identified as indispensable players in lymphatic development, including the Hippo pathway effectors YAP and TAZ, and extracellular matrix protein Polydom/Svep1, which is a ligand of α9β1.

    Compelling evidence of nonvenous-derived lymphatics are largely drawn from lineage tracing studies. For the intestine, Pitx2 (paired-liked homodomain transcription factor-2)-deficient mouse lack Prox1-positive dorsal mesenteric lymphatic vessels, but retain the venous-derived lymphatics alongside the cranial mesenteric artery, indicating the dual origin of mesenteric lymphatic vessels.27 Further cKit lineage tracing experiments have identified hemogenic endothelium-derived cells as an additional source of mesenteric lymphatics.28 For the skin, although most cervical and thoracic dermal lymphatics are descent from venous-derived lymph sacs, one-third of those in the lumbar region were not traced by Tie2-labeled venous endothelium.29 One potential nonvenous source of skin lymphatics is from PROX1-positive clusters that arise in the embryonic dermal blood capillary plexus during a narrow developmental window (E12.5–14.5), which further expand to join the growing lymphatic system. But to trace back, dermal lymphatic endothelial cells transdifferentiated from venous and dermal capillary progenitor populations do share a common origin from a Pax3+ (paired box gene 3) paraxial mesoderm-derived lineage.22

    It is generally accepted that heart carries an extensive lymphatic network. Although the existence of cardiac lymphatic vessels was first described by Rudbeck as early as in 1653, the mechanism of their development has been poorly understood for many years. Studies on rodents and avian showed that the development of cardiac lymphatics is later than the formation of blood vessels during embryogenesis. In the mouse for instance, Klotz et al30 used whole-mount staining methods on E10.5 embryos and hearts isolated at E12.5 to postnatal day (P) 15 to study the spatiotemporal pattern of lymphatic system formation. Whole-mount E10.5 embryos immunostained for endomucin, Prox1, and VEGFR-3 showed that Prox1/VEGFR-3+ endothelial cells emerged from the common cardinal vein, migrating towards the sinus venosus. Staining of hearts isolated at E12.5 revealed an emergence of lymphatic vessel on the ventral side along the outflow tract. At E14.5, cardiac lymphatics vessels sprouting from the region of the sinus venosus emerged on the dorsal side of the heart. At E16.5, the major dorsal vessels expanded downward from the sinus venosus, whereas small vessels appeared between the atria. The cardiac lymphatics covered a large part of the surface of the heart by P10, reaching fully developed by P1530 (Figure 1). However, as opposed to the traditional view, cardiac lymphatics also involve nonvenous progenitors from hemogenic endothelium and second heart field,31 and they are heterogeneous with respect to regional difference of origin and formation dynamics. It is now clear that second heart field lineages critically contribute to the ventral cardiac lymphatics independent of the general wave of lymphatic specification from the common cardiac vein,31 highlighting the spatial and temporal complexity of lymphatic development in the heart.

    Figure 1.

    Figure 1. Development of cardiac lymphatics in mouse embryo. The development of cardiac lymphatics begins at embryonic day (E) 10.5 and reaches fully developed by postnatal day (P) 15. Prox1 (prospero homeobox 1)/VEGFR (vascular endothelial growth factor receptor)-3+ lymphatic endothelial cells emerge from the common cardinal vein, migrating towards the sinus venosus at E10.5. At E14.5, cardiac lymphatics first sprouts from the region of the sinus venosus and emerges on the dorsal side of the heart. The major dorsal vessels expand downward from the sinus venosus to form an extensive network at E16.5. The cardiac lymphatics reach fully developed, covering the majority of the surface of the heart by P15. The schematic figure was drawn based on the findings of previous publications listed in the references Srinivasan et al,24 Bos et al,25 and Jeltsch et al.26

    Atherosclerosis

    Atherosclerosis is a chronic inflammatory condition featured by the influx, oxidization, and retention of apoB-containing lipoproteins within the intima.32,33 It has long been documented that lymphatics are present in the adventitial regions of an artery.34 In the context of atherosclerosis, lymphatics are predominantly located in the adventitia but could also be found within the atherosclerotic intima, albeit infrequently.35,36 Above morphological links prompted researchers to uncover the role of lymphatics during the pathogenesis of atherosclerosis in the last few years. Indeed, transgenic mouse strains with lymphatic insufficiency (sVEGFR-3 [soluble VEGFR-3] and Chy) crossed to atherosclerotic mice (LDLR [low-density lipoprotein receptor]−/−/ApoB100/100), sVEGFR-3×LDLR−/−/ApoB100/100 and Chy×LDLR−/−/ApoB100/100 mice, displayed higher levels of atherogenic lipoproteins and faster progression of atherosclerosis than LDLR−/−/ApoB100/100 controls.37 However, enhanced lymphatic vessel function was observed in athero-protected proprotein convertase subtilisin/kexin type 9−/− mice,38 indicating lymphatic-dependent mechanism in modulating cholesterol homeostasis during pathogenesis of atherosclerosis.

    Recent studies found that lymphatic vessels serve as essential conduits during the reverse cholesterol transport, of which peripheral cholesterol including those localized in atherosclerotic plaques are mobilized and transported back to liver for excretion.33 Reverse cholesterol transport maintains lipid homeostasis and protects against atherosclerosis.39–41 This process starts from cellular cholesterol efflux to HDL (high-density lipoprotein) particle through the action of transporters, such as ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1).41,42 Mouse model showed both surgical ablation of lymphatic vessels and genetic ablation using Chy mice, haploinsufficient VEGFR-3 mutants, disrupts reverse cholesterol transport from the skin.43 Using anti-VEGFR-3 monoclonal antibodies that attenuate lymphatic vessel growth also impaired reverse cholesterol transport of [2H]6-labeled cholesterol from atherosclerotic aorta in Apoe–/– mice.43 Of note, the removal of cholesterol by lymphatic vessels seems to be an active process rather than passively uptaking and draining macromolecules and fluid. Lymphatic endothelial cells express functional HDL transporters including the SR-BI (scavenger receptor class B member 1) and ABCA1.44 Blocking SR-BI significantly inhibited reverse cholesterol transport and HDL transport,45 implicating lymphatic transport of HDL via SR-BI transporters is a specific and critical process. In addition, lymphatic system may ameliorate inflammation in atherosclerotic plaques by draining inflammatory cells and cytokines, as indicated by a recent study that surgical disruption of lymphatic vessels aggravated T-cell accumulation inside the atherosclerotic lesion and adventitia, leading to deterioration of atherosclerosis.46

    An important issue of the impact of lymphatic system in the pathogenesis of atherosclerosis is whether it enhances or reduces plaque instability in the later stage of the disease. It is well known that plaque instability is crucial for clinic complication including sudden death.47–50 Pathologically, stable plaque mainly contains smooth muscle cells and fibrotic tissues,51,52 whereas unstable lesions are composed of necrotic core and inflammatory components.53–55 In the adventitia, abundant vessels directly penetrates into the media and basal part of atherosclerotic plaque, where they may play a role in transporting inflammatory cells, nutrition, and lipids.56 Obviously, the presence of micro-blood vessels has been well recognized within atherosclerotic arterial wall, although their impact on plaque instability remains to be established. However, it is unknown whether lymphatic vessels can transport the debris and lipids away from lesions to stabilize the plaque. It would be much interesting to clarify this issue using a state-of-art technique in near future.

    Based on the essential interplay between lymphatics and atherosclerosis, induction of perivascular lymph-angiogenesis using biomedical agents may serve as a therapeutic strategy against atherosclerosis. Injections of a mutant form of VEGF-C (VEGF-C 152s), a VEGFR-3 agonist, improved lymphatic molecular transport in atherosclerotic Ldlr−/− mice and limited plaque formation and improved inflammatory cell migration.57 Application of low-dose lipid-free apoA-I in Ldlr−/− mice enhanced lymphatic density and transportation and abrogated collecting lymphatics vessel permeability.58 In addition, other nonclassical, VEGF-C/D independent, for example, CXCL12/CXCR4-mediated, lymph-angiogenesis may also constitute potential therapeutic targets.46 Overall, these findings indicate that lymphatics exert their role not only in the pathogenesis of atherosclerosis but also potential therapeutic targets.

    Myocardial infarction occurs when an atherosclerotic plaque ruptures with subsequent thrombus formation, leading to coronary lumen blockage and death of myocardium.59 Although percutaneous coronary intervention is an effective treatment to recanalize occluded coronary arteries, majority of postmyocardial infarction patients still bear a high risk of developing adverse cardiac remodeling and eventually heart failure. Several studies have revealed that myocardial infarction is accompanied by cardiac lymph-angiogenesis.30,60,61 Of note, lymph-angiogenesis occurs not only in the infarcted region but also in the noninfarcted region.30,60,61 Klotz et al30 found a significant increase in the expression of VEGFR-3, Lyve1, and Prox1 from 24 hours up to 21 days postmyocardial infarction. At day 7 after myocardial infarction, the branches of surface VEGFR-3+ lymphatic vessels increased significantly, and the diameter and density of lymphatic vessels at the border zone of the infarct/scar region increased significantly by day 14 after myocardial infarction. However, despite the increased number of lymphatic vessels in the peri-infarcted area postmyocardial infarction, epicardial precollector, and collector lymphatics were adversely remodeled. As a result, the deterioration of cardiac lymph transport capacity further aggravates myocardial edema and cardiac dysfunction.61 Even after timely treating myocardial infarction with implantation of drug-eluting stent, dysfunction of cardiac lymphatic would cause stent-induced coronary hyper-constricting response, partially offsetting the efficacy of percutaneous coronary intervention.62

    Therapeutic stimulation of cardiac lymph-angiogenesis seems to be beneficial to the recovery of cardiac function after myocardial infarction.30,61 Treating wild-type or Vegfr3lacZ/+reporter mice with VEGFR-3–specific recombinant protein VEGF-C156S can effectively improve cardiac function postmyocardial infarction, reflected by smaller ventricular end-systolic volumes and increased ejection fraction.30 In another study, Henri et al61 showed that by using albumin-alginate particles, intramyocardial targeted delivery of VEGFR-3-selective agonist VEGF-C 152s, accelerated cardiac lymph-angiogenesis in a dose-dependent manner and limited precollector lymphatics remodeling after myocardial infarction, resulting in improvement of myocardial fluid balance and relief of cardiac inflammation, fibrosis, and dysfunction. Furthermore, Vieira et al63 revealed that using VEGF-C to stimulate lymph-angiogenesis enhanced the clearance of immune cells and reduced the inflammatory response postmyocardial infarction in a process dependent on Lyve1. Moreover, evidence is emerging that several cardioprotective peptides have much to offer in counteracting pathological remodeling of lymphatic vasculature after myocardial infarction. Overexpression of adrenomedullin, a vasodilator from the calcitonin peptide family and essential for lymphatic development and stabilization,64 increased lymph-angiogenesis and cardiac function post-myocardial infarction, and relieved cardiac edema.65 Apelin, as a bioactive peptide for angiogenesis and cardiac contractility, protects the lymphatic vasculature organization, partially by regulating the secretion of sphingosine-1-phosphate in lymphatic endothelial cells and maintaining the integrity of cellular junctions.66 To sum up, the cardiac lymphatic system is beneficial in reducing cardiac edema and inflammation postmyocardial infarction, contributing to the cardiac function recovery (Figure 2). Therefore, therapeutic induction of lymph-angiogenesis may be an appealing approach for the treatment of ischemic heart disease.

    Figure 2.

    Figure 2. Cardiac lymphatics in ischemic tissues. Tissues from untreated and left coronary artery ligation heart of mice were harvested and immunostained with antibodies against lymph-endothelial cell marker Lyve1 (lymphatic vessel endothelial hyaluronan receptor 1; red) and fibroblast marker CD90 (green) for nucleus staining with DAPI (nuclei marker 4',6-diamidino-2-phenylindole; blue; unpublished data). In normal heart tissue there is a few lymphatics (red, left), which is significantly increased after ischemic/reperfusion injury (red color, middle). This is not only increased number but also altered gene expression profile (right, schematic presentation), which is related to functional changes during the disease status.

    Hypertension

    Essential hypertension has a complex pathophysiology involving the interplay of genetic predispositions and environmental factors.67–69 There are several factors influencing blood pressure and hypertension. Angiotensin-related vessel constriction may be one crucial factor.67,70 However, it is believed that a major contributing factor is dysregulation of body fluid resulting in excessive retention of sodium and water.71 Traditional 2-compartment model assumes sodium are distributed mainly to intravascular and interstitial space. The skin, however, as the largest human organ forming a significant component of body interstitium, is now recognized as the third compartment for sodium storage and buffering, and is relevant to the modulation of blood pressure.72

    Clinical skin specimen showed increased cutaneous sodium content and lymphatic vessels but decreased expression of VEGF-C in patients with hypertension than those who are normotensive.73 High-salt diet fed in rats increased skin lymph-angiogenesis and endothelial nitric oxide synthase expression through the activation of tonicity-responsive enhancer-binding protein–VEGF-C signaling in mononuclear phagocyte system cells.74 The expanded lymphatic network consequently facilitates lymph formation and enhanced expression of various chemoattractants, for example, CCL21.75 Importantly, lymphatic network induced by salt accumulation is functional as augmented lymph flow in skin and muscle were observed ex vivo using advanced imaging tracing technique.76 Deleting tonicity-responsive enhancer-binding protein in macrophages or blocking VEGFR-3 both inhibited lymphatic capillary density and induced salt-sensitive hypertension, underscoring the role of cutaneous lymphatic homeostatic in internal sodium buffering and blood pressure regulation.74,77

    Renal function has also been identified as a partial cause of hypertension in human and rodents.78–80 As lymphatic vessels are crucial for clearing fluid, chemokines, and immune cells, they serve as a potential target for resolving inflammation and modulating blood pressure. Genetic induction of lymph-angiogenesis by kidney-specific overexpression of murine VEGF-D reduced renal immune cell accumulation and prevented various types of hypertension, including salt-sensitive, nitric oxide synthase inhibition–induced81 and angiotensin II-induced hypertension.82 Similarly, VEGF-C administration enhanced renal lymph-angiogenesis and attenuated renal inflammation, thus exerting an antihypertensive effect.83

    Heart Transplantation

    Cardiac transplantation remains the last resort for end-stage heart disease. However, chronic rejection, including cardiac allograft vasculopathy, remains a major impediment to long-term survival after heart transplantation. As much as around 30% of patients develop allograft vasculopathy by 5 years posttransplant, and allograft vasculopathy is the major cause of death and graft loss.84 Since donor lymphatic vessels are not surgically anastomosed to that of host during heart transplantation due to technical challenges, perturbed lymphatic drainage may be a mechanism underlying allograft rejection. In fact, endomyocardial biopsies showed that heart transplant recipients with episode of clinically relevant rejection had a significantly lower density of VEGFR-3 expression on myocardial lymphatic endothelium at 2 weeks after transplantation,85 but lymphatic network would gradually become reconnected posttransplantation.86 Together with de novo lymphatic regeneration, reconstructed lymphatic network facilitates the migration of antigen-presenting cells to draining lymphoid organs.

    In rat cardiac allograft model, chronic rejection induced growth of donor cells-derived lymphatic vessels with enhanced expression of VEGFR-3 and dendritic cell chemokine CCL21.87 Interestingly, inhibiting VEGF-C/D/VEGFR-3 signaling using adenoviral VEGFR-3-Ig did not affect allograft lymph-angiogenesis, but rather reduced dendritic cell recruitment and entry of CD8+ effectors into the allograft, and thus prolonged cardiac allograft survival.87 A recent ex vivo study using single-photon emission computed tomography/computed tomography of lymphoscintigraphy provided objective evidence that lymphatic flow to the mediastinal lymph nodes is increased following heart transplantation, and is correlated with enhanced CD8+/CD4+ T cells and CD68+ macrophages infiltration in cardiac graft.88 Moreover, the ischemic cold preservation and subsequent ischemia-reperfusion injury before transplantation is also associated with lymphatic endothelial activation. Pharmacological blocking of VEGF-C/VEGFR-3 reduces acute and chronic rejection, allograft vasculopathy, and cardiac fibrosis, improving allograft survival.89 Thus, targeted delivery of immune therapeutics to lymph nodes offer an unprecedented opportunity to improve the outcomes of heart transplantation.

    Summary and Perspectives

    Over the past 20 years, with the identification of specific lymphatic markers and advancement of genetic and imaging techniques, rapid progress has been made in understanding the anatomy, development, and physiological functions of the lymphatic system. Elucidating the mechanisms of how lymphatics impact on the pathogenesis and pathophysiology of various cardiovascular diseases offer novel therapeutic targets that complements our current treatment options. For example, promoting lymph-angiogenesis with VEGF-C in the postmyocardial infarction heart may improve myocardial edema and cardiac remodeling, whereas attenuating lymphatic formation with monoclonal antibody of VEGFR-3 after heart transplantation can reduce allograft rejection and allograft vasculopathy. However, certain issues warrant further research. For instance, whether lymphatic heterogeneity with respect to the origin affects their biological behavior such as regeneration potential. Recently, several reports indicate the presence of vascular stem/progenitor cells in the vessel wall of a variety of tissues in adults.90,91 These progenitors display an ability of angiogenesis, endothelial repair in large arteries, inflammatory response, smooth muscle cell accumulation, and fibrosis of injured vessels.92 Is it also true for lymphatic vessels to be regenerated from stem/progenitor cells in pathological status? What is the source of lymph-angiogenesis post tissue injury. If we could answer these questions, it might be helpful for treatment of cardiovascular diseases. Thus, only after gaining comprehensive insights into lymphatic biology can we begin to adopt the lymphatic-targeted therapies to treat cardiovascular disorders.

    Nonstandard Abbreviations and Acronyms

    ABCA1

    ATP-binding cassette transporter A1

    ABCG1

    ATP-binding cassette transporter G1

    HDL

    high-density lipoprotein

    LDLR

    low-density lipoprotein receptor

    Lyve1

    lymphatic vessel endothelial hyaluronan receptor 1

    P

    postnatal day

    Pdpn

    podoplanin

    Sox18

    SRY-box 18

    SR-BI

    scavenger receptor class B member 1

    sVEGFR-3

    soluble VEGFR-3

    VEGFR

    vascular endothelial growth factor receptor

    Footnotes

    *These authors contributed equally to this article as co-first authors.

    For Sources of Funding and Disclosures, see page e281.

    Correspondence to: Qingbo Xu, MD, PhD, Department of Cardiology, the First Affiliated Hospital, Zhejiang University, 79 Qingchun Rd, Hangzhou 310003, Zhejiang, China. Email
    Xiaosheng Hu, MD, Department of Cardiology, the First Affiliated Hospital, Zhejiang University, 79 Qingchun Rd, Hangzhou 310003, Zhejiang, China, Email

    References

    • 1. Kerjaschki D. The lymphatic vasculature revisited.J Clin Invest. 2014; 124:874–877. doi: 10.1172/JCI74854CrossrefMedlineGoogle Scholar
    • 2. Morfoisse F, Tatin F, Chaput B, Therville N, Vaysse C, Métivier R, Malloizel-Delaunay J, Pujol F, Godet AC, De Toni F, et al. Lymphatic vasculature requires estrogen receptor-α signaling to protect from lymphedema.Arterioscler Thromb Vasc Biol. 2018; 38:1346–1357. doi: 10.1161/ATVBAHA.118.310997LinkGoogle Scholar
    • 3. Tirronen A, Vuorio T, Kettunen S, Hokkanen K, Ramms B, Niskanen H, Laakso H, Kaikkonen MU, Jauhiainen M, Gordts PLSM, et al. Deletion of lymphangiogenic and angiogenic growth factor VEGF-D leads to severe hyperlipidemia and delayed clearance of chylomicron remnants.Arterioscler Thromb Vasc Biol. 2018; 38:2327–2337. doi: 10.1161/ATVBAHA.118.311549LinkGoogle Scholar
    • 4. Gu W, Ni Z, Tan YQ, Deng J, Zhang SJ, Lv ZC, Wang XJ, Chen T, Zhang Z, Hu Y, et al. Adventitial cell atlas of wt (Wild Type) and ApoE (Apolipoprotein E)-deficient mice defined by single-cell RNA sequencing.Arterioscler Thromb Vasc Biol. 2019; 39:1055–1071. doi: 10.1161/ATVBAHA.119.312399LinkGoogle Scholar
    • 5. Ali Z, Mukwaya A, Biesemeier A, Ntzouni M, Ramsköld D, Giatrellis S, Mammadzada P, Cao R, Lennikov A, Marass M, et al. Intussusceptive vascular remodeling precedes pathological neovascularization.Arterioscler Thromb Vasc Biol. 2019; 39:1402–1418. doi: 10.1161/ATVBAHA.118.312190LinkGoogle Scholar
    • 6. Russo E, Teijeira A, Vaahtomeri K, Willrodt AH, Bloch JS, Nitschké M, Santambrogio L, Kerjaschki D, Sixt M, Halin C. Intralymphatic CCL21 promotes tissue egress of dendritic cells through afferent lymphatic vessels.Cell Rep. 2016; 14:1723–1734. doi: 10.1016/j.celrep.2016.01.048CrossrefMedlineGoogle Scholar
    • 7. van der Vorst EPC, Weber C. Novel features of monocytes and macrophages in cardiovascular biology and disease.Arterioscler Thromb Vasc Biol. 2019; 39:e30–e37. doi: 10.1161/ATVBAHA.118.312002LinkGoogle Scholar
    • 8. Sacchi G, Weber E, Comparini L. Histological framework of lymphatic vasa vasorum of major arteries: an experimental study.Lymphology. 1990; 23:135–139.MedlineGoogle Scholar
    • 9. Drozdz K, Janczak D, Dziegiel P, Podhorska M, Patrzałek D, Ziółkowski P, Andrzejak R, Szuba A. Adventitial lymphatics of internal carotid artery in healthy and atherosclerotic vessels.Folia Histochem Cytobiol. 2008; 46:433–436. doi: 10.2478/v10042-008-0083-7MedlineGoogle Scholar
    • 10. Majesky MW. Vascular development.Arterioscler Thromb Vasc Biol. 2018; 38:e17–e24. doi: 10.1161/ATVBAHA.118.310223LinkGoogle Scholar
    • 11. Cui Y. Impact of lymphatic vessels on the heart.Thorac Cardiovasc Surg. 2010; 58:1–7. doi: 10.1055/s-0029-1240553CrossrefMedlineGoogle Scholar
    • 12. Miller AJ, Pick R, Katz LN. The importance of the lymphatics of the mammalian heart: experimental observations and some speculations.Circulation. 1964; 29:SUPPL:485–SUPPL:487. doi: 10.1161/01.cir.29.4.485LinkGoogle Scholar
    • 13. Shimada T, Noguchi T, Takita K, Kitamura H, Nakamura M. Morphology of lymphatics of the mammalian heart with special reference to the architecture and distribution of the subepicardial lymphatic system.Acta Anat (Basel). 1989; 136:16–20. doi: 10.1159/000146791CrossrefMedlineGoogle Scholar
    • 14. Mehlhorn U, Davis KL, Burke EJ, Adams D, Laine GA, Allen SJ. Impact of cardiopulmonary bypass and cardioplegic arrest on myocardial lymphatic function.Am J Physiol. 1995; 268(1 Pt 2):H178–H183. doi: 10.1152/ajpheart.1995.268.1.H178MedlineGoogle Scholar
    • 15. Escobedo N, Oliver G. Lymphangiogenesis: origin, specification, and cell fate determination.Annu Rev Cell Dev Biol. 2016; 32:677–691. doi: 10.1146/annurev-cellbio-111315-124944CrossrefMedlineGoogle Scholar
    • 16. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle.Cardiovasc Res. 2010; 87:198–210. doi: 10.1093/cvr/cvq062CrossrefMedlineGoogle Scholar
    • 17. Phan CT, Tso P. Intestinal lipid absorption and transport.Front Biosci. 2001; 6:D299–D319. doi: 10.2741/phanCrossrefMedlineGoogle Scholar
    • 18. Iqbal J, Hussain MM. Intestinal lipid absorption.Am J Physiol Endocrinol Metab. 2009; 296:E1183–E1194. doi: 10.1152/ajpendo.90899.2008CrossrefMedlineGoogle Scholar
    • 19. Gur-Cohen S, Yang H, Baksh SC, Miao Y, Levorse J, Kataru RP, Liu X, de la Cruz-Racelis J, Mehrara BJ, Fuchs E. Stem cell-driven lymphatic remodeling coordinates tissue regeneration.Science. 2019; 366:1218–1225. doi: 10.1126/science.aay4509CrossrefMedlineGoogle Scholar
    • 20. Sabin FR. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig.Am J Anat. 1902; 1:367–389.CrossrefGoogle Scholar
    • 21. Huntington GS, McClure CFW. The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica).Am J Anat. 1910; 10:177–312.CrossrefGoogle Scholar
    • 22. Stone OA, Stainier DYR. Paraxial mesoderm is the major source of lymphatic endothelium.Dev Cell. 2019; 50:247–255.e3. doi: 10.1016/j.devcel.2019.04.034CrossrefMedlineGoogle Scholar
    • 23. Yang Y, García-Verdugo JM, Soriano-Navarro M, Srinivasan RS, Scallan JP, Singh MK, Epstein JA, Oliver G. Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos.Blood. 2012; 120:2340–2348. doi: 10.1182/blood-2012-05-428607CrossrefMedlineGoogle Scholar
    • 24. Srinivasan RS, Escobedo N, Yang Y, Interiano A, Dillard ME, Finkelstein D, Mukatira S, Gil HJ, Nurmi H, Alitalo K, et al. The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors.Genes Dev. 2014; 28:2175–2187. doi: 10.1101/gad.216226.113CrossrefMedlineGoogle Scholar
    • 25. Bos FL, Caunt M, Peterson-Maduro J, Planas-Paz L, Kowalski J, Karpanen T, van Impel A, Tong R, Ernst JA, Korving J, et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo.Circ Res. 2011; 109:486–491. doi: 10.1161/CIRCRESAHA.111.250738LinkGoogle Scholar
    • 26. Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation.Circulation. 2014; 129:1962–1971. doi: 10.1161/CIRCULATIONAHA.113.002779LinkGoogle Scholar
    • 27. Mahadevan A, Welsh IC, Sivakumar A, Gludish DW, Shilvock AR, Noden DM, Huss D, Lansford R, Kurpios NA. The left-right Pitx2 pathway drives organ-specific arterial and lymphatic development in the intestine.Dev Cell. 2014; 31:690–706. doi: 10.1016/j.devcel.2014.11.002CrossrefMedlineGoogle Scholar
    • 28. Stanczuk L, Martinez-Corral I, Ulvmar MH, Zhang Y, Laviña B, Fruttiger M, Adams RH, Saur D, Betsholtz C, Ortega S, et al. cKit lineage hemogenic endothelium-derived cells contribute to mesenteric lymphatic vessels.Cell Rep. 2015; 10:1708–1721. doi: 10.1016/j.celrep.2015.02.026CrossrefMedlineGoogle Scholar
    • 29. Martinez-Corral I, Ulvmar MH, Stanczuk L, Tatin F, Kizhatil K, John SW, Alitalo K, Ortega S, Makinen T. Nonvenous origin of dermal lymphatic vasculature.Circ Res. 2015; 116:1649–1654. doi: 10.1161/CIRCRESAHA.116.306170LinkGoogle Scholar
    • 30. Klotz L, Norman S, Vieira JM, Masters M, Rohling M, Dubé KN, Bollini S, Matsuzaki F, Carr CA, Riley PR. Cardiac lymphatics are heterogeneous in origin and respond to injury.Nature. 2015; 522:62–67. doi: 10.1038/nature14483CrossrefMedlineGoogle Scholar
    • 31. Lioux G, Liu X, Temiño S, Oxendine M, Ayala E, Ortega S, Kelly RG, Oliver G, Torres M. A second heart field-derived vasculogenic niche contributes to cardiac lymphatics.Dev Cell. 2020; 52:350–363.e6. doi: 10.1016/j.devcel.2019.12.006CrossrefMedlineGoogle Scholar
    • 32. Davis FM, Gallagher KA. Epigenetic mechanisms in monocytes/macrophages regulate inflammation in cardiometabolic and vascular disease.Arterioscler Thromb Vasc Biol. 2019; 39:623–634. doi: 10.1161/ATVBAHA.118.312135LinkGoogle Scholar
    • 33. Barrett TJ. Macrophages in atherosclerosis regression.Arterioscler Thromb Vasc Biol. 2020; 40:20–33. doi: 10.1161/ATVBAHA.119.312802LinkGoogle Scholar
    • 34. Hoggan G, Hoggan FE. The lymphatics of the walls of the larger blood-vessels and lymphatics.J Anat Physiol. 1882; 17:1–23.MedlineGoogle Scholar
    • 35. Nakano T, Nakashima Y, Yonemitsu Y, Sumiyoshi S, Chen YX, Akishima Y, Ishii T, Iida M, Sueishi K. Angiogenesis and lymphangiogenesis and expression of lymphangiogenic factors in the atherosclerotic intima of human coronary arteries.Hum Pathol. 2005; 36:330–340. doi: 10.1016/j.humpath.2005.01.001CrossrefMedlineGoogle Scholar
    • 36. Kutkut I, Meens MJ, McKee TA, Bochaton-Piallat ML, Kwak BR. Lymphatic vessels: an emerging actor in atherosclerotic plaque development.Eur J Clin Invest. 2015; 45:100–108. doi: 10.1111/eci.12372CrossrefMedlineGoogle Scholar
    • 37. Vuorio T, Nurmi H, Moulton K, Kurkipuro J, Robciuc MR, Ohman M, Heinonen SE, Samaranayake H, Heikura T, Alitalo K, et al. Lymphatic vessel insufficiency in hypercholesterolemic mice alters lipoprotein levels and promotes atherogenesis.Arterioscler Thromb Vasc Biol. 2014; 34:1162–1170. doi: 10.1161/ATVBAHA.114.302528LinkGoogle Scholar
    • 38. Milasan A, Dallaire F, Mayer G, Martel C. Effects of LDL receptor modulation on lymphatic function.Sci Rep. 2016; 6:27862. doi: 10.1038/srep27862CrossrefMedlineGoogle Scholar
    • 39. Rohatgi A. Reverse cholesterol transport and atherosclerosis.Arterioscler Thromb Vasc Biol. 2019; 39:2–4. doi: 10.1161/ATVBAHA.118.311978LinkGoogle Scholar
    • 40. Bowden KL, Dubland JA, Chan T, Xu YH, Grabowski GA, Du H, Francis GA. LAL (Lysosomal Acid Lipase) promotes reverse cholesterol transport in vitro and in vivo.Arterioscler Thromb Vasc Biol. 2018; 38:1191–1201. doi: 10.1161/ATVBAHA.117.310507LinkGoogle Scholar
    • 41. Takiguchi S, Ayaori M, Yakushiji E, Nishida T, Nakaya K, Sasaki M, Iizuka M, Uto-Kondo H, Terao Y, Yogo M, et al. Hepatic overexpression of endothelial lipase lowers high-density lipoprotein but maintains reverse cholesterol transport in mice: role of scavenger receptor class B type I/ATP-binding cassette transporter A1-dependent pathways.Arterioscler Thromb Vasc Biol. 2018; 38:1454–1467. doi: 10.1161/ATVBAHA.118.311056LinkGoogle Scholar
    • 42. Sasaki M, Komatsu T, Ikewaki K. Impact of hepatic ABCA1 (ATP-Binding Cassette Transporter A1) deletion on reverse cholesterol transport a new clue in solving complex HDL (High-Density Lipoprotein) metabolism.Arterioscler Thromb Vasc Biol. 2019; 39:1699–1701. doi: 10.1161/ATVBAHA.119.313016LinkGoogle Scholar
    • 43. Martel C, Li W, Fulp B, Platt AM, Gautier EL, Westerterp M, Bittman R, Tall AR, Chen SH, Thomas MJ, et al. Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice.J Clin Invest. 2013; 123:1571–1579. doi: 10.1172/JCI63685CrossrefMedlineGoogle Scholar
    • 44. Lim HY, Thiam CH, Yeo KP, Bisoendial R, Hii CS, McGrath KC, Tan KW, Heather A, Alexander JS, Angeli V. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL.Cell Metab. 2013; 17:671–684. doi: 10.1016/j.cmet.2013.04.002CrossrefMedlineGoogle Scholar
    • 45. Ghaffari S, Naderi Nabi F, Sugiyama MG, Lee WL. Estrogen inhibits LDL (Low-Density Lipoprotein) transcytosis by human coronary artery endothelial cells via GPER (G-Protein-Coupled Estrogen Receptor) and SR-BI (Scavenger Receptor Class B Type 1).Arterioscler Thromb Vasc Biol. 2018; 38:2283–2294. doi: 10.1161/ATVBAHA.118.310792LinkGoogle Scholar
    • 46. Rademakers T, van der Vorst EP, Daissormont IT, Otten JJ, Theodorou K, Theelen TL, Gijbels M, Anisimov A, Nurmi H, Lindeman JH, et al. Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis.Sci Rep. 2017; 7:45263. doi: 10.1038/srep45263CrossrefMedlineGoogle Scholar
    • 47. Chai JT, Ruparelia N, Goel A, Kyriakou T, Biasiolli L, Edgar L, Handa A, Farrall M, Watkins H, Choudhury RP. Differential gene expression in macrophages from human atherosclerotic plaques shows convergence on pathways implicated by genome-wide association study risk variants.Arterioscler Thromb Vasc Biol. 2018; 38:2718–2730. doi: 10.1161/ATVBAHA.118.311209LinkGoogle Scholar
    • 48. Steffen BT, Guan W, Stein JH, Tattersall MC, Kaufman JD, Sandfort V, Szklo M, Tsai MY. Plasma n-3 and n-6 fatty acids are differentially related to carotid plaque and its progression: the multi-ethnic study of atherosclerosis.Arterioscler Thromb Vasc Biol. 2018; 38:653–659. doi: 10.1161/ATVBAHA.117.310366LinkGoogle Scholar
    • 49. Karamariti E, Zhai C, Yu B, Qiao L, Wang Z, Potter CMF, Wong MM, Simpson RML, Zhang Z, Wang X, et al. DKK3 (Dickkopf 3) alters atherosclerotic plaque phenotype involving vascular progenitor and fibroblast differentiation into smooth muscle cells.Arterioscler Thromb Vasc Biol. 2018; 38:425–437. doi: 10.1161/ATVBAHA.117.310079LinkGoogle Scholar
    • 50. Zhou C, Yuan C, Li R, Wang W, Li C, Zhao X; CARE-II Study Collaborators. Association between incomplete circle of willis and carotid vulnerable atherosclerotic plaques.Arterioscler Thromb Vasc Biol. 2018; 38:2744–2749. doi: 10.1161/ATVBAHA.118.311797LinkGoogle Scholar
    • 51. Doddapattar P, Jain M, Dhanesha N, Lentz SR, Chauhan AK. Fibronectin containing extra domain a induces plaque destabilization in the innominate artery of aged apolipoprotein E-deficient mice.Arterioscler Thromb Vasc Biol. 2018; 38:500–508. doi: 10.1161/ATVBAHA.117.310345LinkGoogle Scholar
    • 52. Liu M, Gomez D. Smooth muscle cell phenotypic diversity.Arterioscler Thromb Vasc Biol. 2019; 39:1715–1723. doi: 10.1161/ATVBAHA.119.312131LinkGoogle Scholar
    • 53. Williams JW, Martel C, Potteaux S, Esaulova E, Ingersoll MA, Elvington A, Saunders BT, Huang LH, Habenicht AJ, Zinselmeyer BH, et al. Limited macrophage positional dynamics in progressing or regressing murine atherosclerotic plaques-brief report.Arterioscler Thromb Vasc Biol. 2018; 38:1702–1710. doi: 10.1161/ATVBAHA.118.311319LinkGoogle Scholar
    • 54. Wilson JM, Nguyen AT, Schuyler AJ, Commins SP, Taylor AM, Platts-Mills TAE, McNamara CA. IgE to the mammalian oligosaccharide galactose-α-1,3-galactose is associated with increased atheroma volume and plaques with unstable characteristics-brief report.Arterioscler Thromb Vasc Biol. 2018; 38:1665–1669. doi: 10.1161/ATVBAHA.118.311222LinkGoogle Scholar
    • 55. Li W, Luehmann HP, Hsiao HM, Tanaka S, Higashikubo R, Gauthier JM, Sultan D, Lavine KJ, Brody SL, Gelman AE, et al. Visualization of monocytic cells in regressing atherosclerotic plaques by intravital 2-photon and positron emission tomography-based imaging-brief report.Arterioscler Thromb Vasc Biol. 2018; 38:1030–1036. doi: 10.1161/ATVBAHA.117.310517LinkGoogle Scholar
    • 56. Di Bartolo BA, Psaltis PJ, Bursill CA, Nicholls SJ. Translating evidence of HDL and plaque regression.Arterioscler Thromb Vasc Biol. 2018; 38:1961–1968. doi: 10.1161/ATVBAHA.118.307026LinkGoogle Scholar
    • 57. Milasan A, Smaani A, Martel C. Early rescue of lymphatic function limits atherosclerosis progression in Ldlr-/- mice.Atherosclerosis. 2019; 283:106–119. doi: 10.1016/j.atherosclerosis.2019.01.031CrossrefMedlineGoogle Scholar
    • 58. Milasan A, Jean G, Dallaire F, Tardif JC, Merhi Y, Sorci-Thomas M, Martel C. Apolipoprotein A-I modulates atherosclerosis through lymphatic vessel-dependent mechanisms in mice.J Am Heart Assoc. 2017; 6:e006892.LinkGoogle Scholar
    • 59. Palasubramaniam J, Wang X, Peter K. Myocardial infarction-from atherosclerosis to thrombosis.Arterioscler Thromb Vasc Biol. 2019; 39:e176–e185. doi: 10.1161/ATVBAHA.119.312578LinkGoogle Scholar
    • 60. Ishikawa Y, Akishima-Fukasawa Y, Ito K, Akasaka Y, Tanaka M, Shimokawa R, Kimura-Matsumoto M, Morita H, Sato S, Kamata I, et al. Lymphangiogenesis in myocardial remodelling after infarction.Histopathology. 2007; 51:345–353. doi: 10.1111/j.1365-2559.2007.02785.xCrossrefMedlineGoogle Scholar
    • 61. Henri O, Pouehe C, Houssari M, Galas L, Nicol L, Edwards-Lévy F, Henry JP, Dumesnil A, Boukhalfa I, Banquet S, et al. Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction.Circulation. 2016; 133:1484–1497; discussion 1497. doi: 10.1161/CIRCULATIONAHA.115.020143LinkGoogle Scholar
    • 62. Amamizu H, Matsumoto Y, Morosawa S, Ohyama K, Uzuka H, Hirano M, Nishimiya K, Gokon Y, Watanabe-Asaka T, Hayashi M, et al. Cardiac lymphatic dysfunction causes drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo.Arterioscler Thromb Vasc Biol. 2019; 39:741–753. doi: 10.1161/ATVBAHA.119.312396LinkGoogle Scholar
    • 63. Vieira JM, Norman S, Villa Del Campo C, Cahill TJ, Barnette DN, Gunadasa-Rohling M, Johnson LA, Greaves DR, Carr CA, Jackson DG, et al. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction.J Clin Invest. 2018; 128:3402–3412. doi: 10.1172/JCI97192CrossrefMedlineGoogle Scholar
    • 64. Xu W, Wittchen ES, Hoopes SL, Stefanini L, Burridge K, Caron KM. Small GTPase Rap1A/B is required for lymphatic development and adrenomedullin-induced stabilization of lymphatic endothelial junctions.Arterioscler Thromb Vasc Biol. 2018; 38:2410–2422. doi: 10.1161/ATVBAHA.118.311645LinkGoogle Scholar
    • 65. Trincot CE, Xu W, Zhang H, Kulikauskas MR, Caranasos TG, Jensen BC, Sabine A, Petrova TV, Caron KM. Adrenomedullin induces cardiac lymphangiogenesis after myocardial infarction and regulates cardiac edema via connexin 43.Circ Res. 2019; 124:101–113. doi: 10.1161/CIRCRESAHA.118.313835LinkGoogle Scholar
    • 66. Tatin F, Renaud-Gabardos E, Godet AC, Hantelys F, Pujol F, Morfoisse F, Calise D, Viars F, Valet P, Masri B, et al. Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction.JCI Insight. 2017; 2:e93887.CrossrefMedlineGoogle Scholar
    • 67. Helmstädter J, Frenis K, Filippou K, Grill A, Dib M, Kalinovic S, Pawelke F, Kus K, Kröller-Schön S, Oelze M, et al. Endothelial GLP-1 (Glucagon-Like Peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension.Arterioscler Thromb Vasc Biol. 2020; 40:145–158. doi: 10.1161/atv.0000615456.97862.30LinkGoogle Scholar
    • 68. He J, Liu X, Su C, Wu F, Sun J, Zhang J, Yang X, Zhang C, Zhou Z, Zhang X, et al. Inhibition of mitochondrial oxidative damage improves reendothelialization capacity of endothelial progenitor cells via SIRT3 (Sirtuin 3)-enhanced SOD2 (Superoxide Dismutase 2) deacetylation in hypertension.Arterioscler Thromb Vasc Biol. 2019; 39:1682–1698. doi: 10.1161/ATVBAHA.119.312613LinkGoogle Scholar
    • 69. Carnevale D, Facchinello N, Iodice D, Bizzotto D, Perrotta M, De Stefani D, Pallante F, Carnevale L, Ricciardi F, Cifelli G, et al. Loss of EMILIN-1 enhances arteriolar myogenic tone through TGF-β (Transforming Growth Factor-β)-dependent transactivation of EGFR (Epidermal Growth Factor Receptor) and is relevant for hypertension in mice and humans.Arterioscler Thromb Vasc Biol. 2018; 38:2484–2497. doi: 10.1161/ATVBAHA.118.311115LinkGoogle Scholar
    • 70. Brown IAM, Diederich L, Good ME, DeLalio LJ, Murphy SA, Cortese-Krott MM, Hall JL, Le TH, Isakson BE. Vascular smooth muscle remodeling in conductive and resistance arteries in hypertension.Arterioscler Thromb Vasc Biol. 2018; 38:1969–1985. doi: 10.1161/ATVBAHA.118.311229LinkGoogle Scholar
    • 71. Lu S, Strand KA, Mutryn MF, Tucker RM, Jolly AJ, Furgeson SB, Moulton KS, Nemenoff RA, Weiser-Evans MCM. PTEN (Phosphatase and Tensin Homolog) protects against Ang II (Angiotensin II)-induced pathological vascular fibrosis and remodeling-brief report.Arterioscler Thromb Vasc Biol. 2020; 40:394–403. doi: 10.1161/ATVBAHA.119.313757LinkGoogle Scholar
    • 72. Selvarajah V, Connolly K, McEniery C, Wilkinson I. Skin sodium and hypertension: a paradigm shift?Curr Hypertens Rep. 2018; 20:94. doi: 10.1007/s11906-018-0892-9CrossrefMedlineGoogle Scholar
    • 73. Chachaj A, Puła B, Chabowski M, Grzegrzółka J, Szahidewicz-Krupska E, Karczewski M, Janczak D, Dzięgiel P, Podhorska-Okołów M, Mazur G, et al. Role of the lymphatic system in the pathogenesis of hypertension in humans.Lymphat Res Biol. 2018; 16:140–146. doi: 10.1089/lrb.2017.0051CrossrefMedlineGoogle Scholar
    • 74. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Müller DN, Derer W, et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat Med. 2009; 15:545–552. doi: 10.1038/nm.1960CrossrefMedlineGoogle Scholar
    • 75. Karlsen TV, Reikvam T, Tofteberg A, Nikpey E, Skogstrand T, Wagner M, Tenstad O, Wiig H. Lymphangiogenesis facilitates initial lymph formation and enhances the dendritic cell mobilizing chemokine CCL21 without affecting migration.Arterioscler Thromb Vasc Biol. 2017; 37:2128–2135. doi: 10.1161/ATVBAHA.117.309883LinkGoogle Scholar
    • 76. Karlsen TV, Nikpey E, Han J, Reikvam T, Rakova N, Castorena-Gonzalez JA, Davis MJ, Titze JM, Tenstad O, Wiig H. High-salt diet causes expansion of the lymphatic network and increased lymph flow in skin and muscle of rats.Arterioscler Thromb Vasc Biol. 2018; 38:2054–2064. doi: 10.1161/ATVBAHA.118.311149LinkGoogle Scholar
    • 77. Wiig H, Schröder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV, Boschmann M, Goss J, Bry M, Rakova N, et al. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J Clin Invest. 2013; 123:2803–2815. doi: 10.1172/JCI60113CrossrefMedlineGoogle Scholar
    • 78. Liu JJ, Liu S, Gurung RL, Ang K, Ee Tang W, Sum CF, Tavintharan S, Hadjadj S, Lim SC. Arterial stiffness modulates the association of resting heart rate with rapid renal function decline in individuals with type 2 diabetes mellitus.Arterioscler Thromb Vasc Biol. 2019; 39:2437–2444. doi: 10.1161/ATVBAHA.119.313163LinkGoogle Scholar
    • 79. Gupta N, Buffa JA, Roberts AB, Sangwan N, Skye SM, Li L, Ho KJ, Varga J, DiDonato JA, Tang WHW, et al. Targeted inhibition of gut microbial trimethylamine N-oxide production reduces renal tubulointerstitial fibrosis and functional impairment in a murine model of chronic kidney disease.Arterioscler Thromb Vasc Biol. 2020; 40:1239–1255. doi: 10.1161/ATVBAHA.120.314139LinkGoogle Scholar
    • 80. Valdivielso JM, Rodríguez-Puyol D, Pascual J, Barrios C, Bermúdez-López M, Sánchez-Niño MD, Pérez-Fernández M, Ortiz A. Atherosclerosis in chronic kidney disease: more, less, or just different?Arterioscler Thromb Vasc Biol. 2019; 39:1938–1966. doi: 10.1161/ATVBAHA.119.312705LinkGoogle Scholar
    • 81. Lopez Gelston CA, Balasubbramanian D, Abouelkheir GR, Lopez AH, Hudson KR, Johnson ER, Muthuchamy M, Mitchell BM, Rutkowski JM. Enhancing renal lymphatic expansion prevents hypertension in mice.Circ Res. 2018; 122:1094–1101. doi: 10.1161/CIRCRESAHA.118.312765LinkGoogle Scholar
    • 82. Balasubbramanian D, Gelston CAL, Lopez AH, Iskander G, Tate W, Holderness H, Rutkowski JM, Mitchell BM. Augmenting renal lymphatic density prevents angiotensin II-induced hypertension in male and female mice.Am J Hypertens. 2020; 33:61–69. doi: 10.1093/ajh/hpz139CrossrefMedlineGoogle Scholar
    • 83. Beaini S, Saliba Y, Hajal J, Smayra V, Bakhos JJ, Joubran N, Chelala D, Fares N. VEGF-C attenuates renal damage in salt-sensitive hypertension.J Cell Physiol. 2019; 234:9616–9630. doi: 10.1002/jcp.27648CrossrefMedlineGoogle Scholar
    • 84. Khush KK, Cherikh WS, Chambers DC, Harhay MO, Hayes D, Hsich E, Meiser B, Potena L, Robinson A, Rossano JW, et al; International Society for Heart and Lung Transplantation. The international thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-sixth adult heart transplantation report - 2019; focus theme: donor and recipient size match.J Heart Lung Transplant. 2019; 38:1056–1066. doi: 10.1016/j.healun.2019.08.004CrossrefMedlineGoogle Scholar
    • 85. Geissler HJ, Dashkevich A, Fischer UM, Fries JW, Kuhn-Régnier F, Addicks K, Mehlhorn U, Bloch W. First year changes of myocardial lymphatic endothelial markers in heart transplant recipients.Eur J Cardiothorac Surg. 2006; 29:767–771. doi: 10.1016/j.ejcts.2005.12.024CrossrefMedlineGoogle Scholar
    • 86. Brown K, Badar A, Sunassee K, Fernandes MA, Shariff H, Jurcevic S, Blower PJ, Sacks SH, Mullen GE, Wong W. SPECT/CT lymphoscintigraphy of heterotopic cardiac grafts reveals novel sites of lymphatic drainage and T cell priming.Am J Transplant. 2011; 11:225–234. doi: 10.1111/j.1600-6143.2010.03388.xCrossrefMedlineGoogle Scholar
    • 87. Nykänen AI, Sandelin H, Krebs R, Keränen MA, Tuuminen R, Kärpänen T, Wu Y, Pytowski B, Koskinen PK, Ylä-Herttuala S, et al. Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts.Circulation. 2010; 121:1413–1422. doi: 10.1161/CIRCULATIONAHA.109.910703LinkGoogle Scholar
    • 88. Edwards LA, Nowocin AK, Jafari NV, Meader LL, Brown K, Sarde A, Lam C, Murray A, Wong W. Chronic rejection of cardiac allografts is associated with increased lymphatic flow and cellular trafficking.Circulation. 2018; 137:488–503. doi: 10.1161/CIRCULATIONAHA.117.028533LinkGoogle Scholar
    • 89. Dashkevich A, Raissadati A, Syrjälä SO, Zarkada G, Keränen MA, Tuuminen R, Krebs R, Anisimov A, Jeltsch M, Leppänen VM, et al. Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts.Am J Transplant. 2016; 16:1160–1172. doi: 10.1111/ajt.13564CrossrefMedlineGoogle Scholar
    • 90. Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice.J Clin Invest. 2004; 113:1258–1265. doi: 10.1172/JCI19628CrossrefMedlineGoogle Scholar
    • 91. Tang J, Wang H, Huang X, Li F, Zhu H, Li Y, He L, Zhang H, Pu W, Liu K, et al. Arterial Sca1+ vascular stem cells generate de Novo smooth muscle for artery repair and regeneration.Cell Stem Cell. 2020; 26:81–96.e4. doi: 10.1016/j.stem.2019.11.010CrossrefMedlineGoogle Scholar
    • 92. Le Bras A, Yu B, Issa Bhaloo S, Hong X, Zhang Z, Hu Y, Xu Q. Adventitial Sca1+ cells transduced with ETV2 are committed to the endothelial fate and improve vascular remodeling after injury.Arterioscler Thromb Vasc Biol. 2018; 38:232–244. doi: 10.1161/ATVBAHA.117.309853LinkGoogle Scholar