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• W3186164565 abstract "The lymphatic vasculature is an active multifaceted regulator of tissue homeostasis, growth, and regeneration.Lymphatic vessels not only have crucial general functions in the maintenance of tissue fluid homeostasis, immune cell trafficking, and reverse cholesterol transport but also exhibit several tissue-specific functions that support vital organ functions.The discovery of causative genes in lymphatic diseases and developmental studies in animal models over the past decades have greatly expanded our understanding of the mechanisms controlling lymphatic vessel development and growth.The mechanisms that maintain lymphatic vessel integrity in adult tissues, and that control vessel repair as well as regeneration upon injury, are poorly characterized but are crucial for understanding the contribution of lymphatic vessels to disease processes. The lymphatic vasculature is emerging as a multifaceted regulator of tissue homeostasis and regeneration. Lymphatic vessels drain fluid, macromolecules, and immune cells from peripheral tissues to lymph nodes (LNs) and the systemic circulation. Their recently uncovered functions extend beyond drainage and include direct modulation of adaptive immunity and paracrine regulation of organ growth. The developmental mechanisms controlling lymphatic vessel growth have been described with increasing precision. It is less clear how the essential functional features of lymphatic vessels are established and maintained. We discuss the mechanisms that maintain lymphatic vessel integrity in adult tissues and control vessel repair and regeneration. This knowledge is crucial for understanding the pathological vessel changes that contribute to disease, and provides an opportunity for therapy development. The lymphatic vasculature is emerging as a multifaceted regulator of tissue homeostasis and regeneration. Lymphatic vessels drain fluid, macromolecules, and immune cells from peripheral tissues to lymph nodes (LNs) and the systemic circulation. Their recently uncovered functions extend beyond drainage and include direct modulation of adaptive immunity and paracrine regulation of organ growth. The developmental mechanisms controlling lymphatic vessel growth have been described with increasing precision. It is less clear how the essential functional features of lymphatic vessels are established and maintained. We discuss the mechanisms that maintain lymphatic vessel integrity in adult tissues and control vessel repair and regeneration. This knowledge is crucial for understanding the pathological vessel changes that contribute to disease, and provides an opportunity for therapy development. The lymphatic vasculature is composed of a blind-ended network of vessels that continuously collect excess interstitial fluid as well as macromolecules, and transport this fluid, now called lymph, via interposed LNs to the bloodstream (Figure 1). Concomitant lymphatic delivery of antigens and immune cells from the peripheral tissues to the LNs is crucial for the initiation of adaptive immune responses [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,2.Oliver G. et al.The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease.Cell. 2020; 182: 270-296Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. Lymphatic vessels and LNs also contribute to innate immunity by limiting pathogen spread through neutralization by LN-resident subcapsular sinus macrophages and recruited neutrophils [3.Kastenmüller W. et al.A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread.Cell. 2012; 150: 1235-1248Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar]. Lymphatic vessels may also directly limit pathogen spread through inflammatory stimuli-induced and tissue factor-dependent focal lymph clotting that transiently occludes collecting vessels [4.Kilarski W.W. et al.Anti-clotting functions of lymphatics form the natural on-off switch for immune recognition by controlling the antigens and immune cells access to the lymph nodes.BioRxiv. 2021; (Published online June 22, 2021. https://doi.org/10.1101/2021.06.22.449446)Google Scholar], and by providing an 'innate-like' barrier to viral dissemination through type I interferon (IFN)-mediated remodeling of lymphatic capillaries to shut down fluid transport [5.Loo C.P. et al.Lymphatic vessels balance viral dissemination and immune activation following cutaneous viral infection.Cell Rep. 2017; 20: 3176-3187Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Lymphatic vessels have additional specialized functions in different organs (Figure 1) [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,2.Oliver G. et al.The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease.Cell. 2020; 182: 270-296Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,6.Petrova T.V. Koh G.Y. Organ-specific lymphatic vasculature: from development to pathophysiology.J. Exp. Med. 2018; 215: 35-49Crossref PubMed Scopus (115) Google Scholar]. For example, lacteals (see Glossary) are blunt-ended lymphatic vessels at the center of intestinal villi that have a unique role in the absorption of dietary fats and fat-soluble vitamins. Dysfunction of lymphatic vessels can lead to chylous effusion in the peritoneal and pleural cavities, and also underlies lymphedema. The latter is characterized by crippling tissue swelling, fibrosis, and increased susceptibility to infections due to accumulation of protein-rich fluid in the interstitial space. Beyond the drainage functions of lymphatic vessels, emerging evidence demonstrates that lymphatic endothelial cells (LECs) have active roles in shaping local immune responses through direct modulation of adaptive immunity, and this is linked to their ability to present antigens for controlling T cell tolerance and immunity [7.Maisel K. et al.Exploiting lymphatic vessels for immunomodulation: rationale, opportunities, and challenges.Adv. Drug Deliv. Rev. 2017; 114: 43-59Crossref PubMed Scopus (50) Google Scholar, 8.Garnier L. et al.Tumor-associated lymphatic vessel features and immunomodulatory functions.Front. Immunol. 2019; 10: 720Crossref PubMed Scopus (28) Google Scholar, 9.Santambrogio L. et al.The antigen processing and presentation machinery in lymphatic endothelial cells.Front. Immunol. 2019; 10: 1033Crossref PubMed Scopus (17) Google Scholar]. LECs also produce paracrine (lymphangiocrine) signals that were recently shown to regulate cardiac growth [10.Liu X. et al.Lymphoangiocrine signals promote cardiac growth and repair.Nature. 2020; 588: 705-711Crossref PubMed Scopus (5) Google Scholar], hair follicle cycling [11.Yoon S.-Y. et al.An important role of cutaneous lymphatic vessels in coordinating and promoting anagen hair follicle growth.PLoS One. 2019; 14e0220341PubMed Google Scholar, 12.Peña-Jimenez D. et al.Lymphatic vessels interact dynamically with the hair follicle stem cell niche during skin regeneration in vivo.EMBO J. 2019; 38e101688Crossref PubMed Scopus (0) Google Scholar, 13.Gur-Cohen S. et al.Stem cell-driven lymphatic remodeling coordinates tissue regeneration.Science. 2019; 366: 1218-1225Crossref PubMed Scopus (36) Google Scholar], and thermogenesis of brown adipose tissue [14.Li J. et al.Neurotensin is an anti-thermogenic peptide produced by lymphatic endothelial cells.Cell Metab. 2021; 33: 1449-1465Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The traditionally viewed passive lymphatic drainage system is thus becoming recognized as an active multifaceted player in many important physiological processes (Figure 1) and in common diseases including autoimmune disease, atherosclerosis, neurodegenerative disorders, and cancer [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,2.Oliver G. et al.The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease.Cell. 2020; 182: 270-296Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar] see Clinician's corner). The mechanisms of lymphatic vessel development and growth have been dissected with increasing molecular and cellular precision during the past two decades, as recently discussed in several excellent reviews [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,2.Oliver G. et al.The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease.Cell. 2020; 182: 270-296Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,15.Ducoli L. Detmar M. Beyond PROX1: transcriptional, epigenetic, and noncoding RNA regulation of lymphatic identity and function.Dev. Cell. 2021; 56: 406-426Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 16.Martin-Almedina S. et al.Development and physiological functions of the lymphatic system – insights from genetic studies of lymphedema.Physiol. Rev. 2021; (Published online January 28, 2021. https://doi.org/10.1152/physrev.00006.2020)Crossref PubMed Google Scholar, 17.Grimm L. Hogan B.M. Network patterning, morphogenesis and growth in lymphatic vascular development.Curr. Top. Dev. Biol. 2021; 143: 151-204Crossref PubMed Scopus (0) Google Scholar]. By contrast, we have only limited understanding of how lymphatic vessels become functionally specialized to fulfill their roles in supporting the unique functions of different organs, and of how their homeostatic functions are maintained in adult tissues. The lymphatic vascular system develops after the establishment of a functional circulatory system. In mice, LECs differentiate from blood endothelial cells (BECs) within major veins at mid-gestation and migrate into the adjacent mesenchyme to form the first primitive lymphatic structures [17.Grimm L. Hogan B.M. Network patterning, morphogenesis and growth in lymphatic vascular development.Curr. Top. Dev. Biol. 2021; 143: 151-204Crossref PubMed Scopus (0) Google Scholar]. Further expansion of the vasculature occurs via lymphangiogenic vessel sprouting. Additional contributions from local and/or non-venous sources of LECs were recently reported in multiple tissues, where lymphvasculogenesis involving assembly from progenitors contributes to vessel formation [18.Jafree D.J. et al.Mechanisms and cell lineages in lymphatic vascular development.Angiogenesis. 2021; 24: 271-288Crossref PubMed Scopus (1) Google Scholar]. The initial lymphatic plexus in each organ subsequently remodels during late gestation or the early postnatal period into a hierarchical network of vessels with specialized functions: blind-ended lymphatic capillaries (also called initial lymphatics), that take up interstitial fluid, and pre-collecting and collecting lymphatic vessels that transport lymph (Figure 2A ). A crucial remodeling process is the formation of luminal valves that establish unidirectional lymph flow in collecting lymphatic vessels [19.Geng X. et al.Intraluminal valves: development, function and disease.Dis. Model. Mech. 2017; 10: 1273-1287Crossref PubMed Scopus (25) Google Scholar]. These vessels also acquire a coverage of smooth muscle cells (SMCs) which, together with skeletal muscles, contract to aid propelling lymph. In addition, they have a basement membrane and continuous zipper junctions to prevent fluid leakage. Lymphatic capillaries instead gain properties that facilitate fluid uptake and the entry of immune cells. These include specialized discontinuous perpendicular button junctions at the interdigitating LEC edges [20.Baluk P. et al.Functionally specialized junctions between endothelial cells of lymphatic vessels.J. Exp. Med. 2007; 204: 2349-2362Crossref PubMed Scopus (577) Google Scholar] as well as anchoring filaments that connect LECs to the interstitial tissue, open the flaps between button junctions upon tissue swelling, and serve as entry point for leukocytes [20.Baluk P. et al.Functionally specialized junctions between endothelial cells of lymphatic vessels.J. Exp. Med. 2007; 204: 2349-2362Crossref PubMed Scopus (577) Google Scholar, 21.Pflicke H. Sixt M. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels.J. Exp. Med. 2009; 206: 2925-2935Crossref PubMed Scopus (193) Google Scholar, 22.Yao L.-C. et al.Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation.Am. J. Pathol. 2012; 180: 2561-2575Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 23.Johnson L.A. et al.Dendritic cells enter lymph vessels by hyaluronan-mediated docking to the endothelial receptor LYVE-1.Nat. Immunol. 2017; 18: 762-770Crossref PubMed Scopus (72) Google Scholar]. The structural and functional specialization of different lymphatic vessel types is now recognized, and the underlying molecular features of LECs are being unveiled by transcriptomic profiling [24.Arasa J. et al.Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation.J. Exp. Med. 2021; 218e20201413Crossref PubMed Scopus (0) Google Scholar,25.Hernández Vásquez M.N. et al.Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels.EMBO J. 2021; 40e107192Crossref PubMed Scopus (0) Google Scholar]. The functional demands of each organ additionally contribute to tissue-specific specialization of the vasculature [6.Petrova T.V. Koh G.Y. Organ-specific lymphatic vasculature: from development to pathophysiology.J. Exp. Med. 2018; 215: 35-49Crossref PubMed Scopus (115) Google Scholar], as exemplified in the intestine (see below), LNs, lung, and meninges (Box 1). Single-cell transcriptomic data of LECs are now available from multiple tissues (e.g., [14.Li J. et al.Neurotensin is an anti-thermogenic peptide produced by lymphatic endothelial cells.Cell Metab. 2021; 33: 1449-1465Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,26.Kalucka J. et al.Single-cell transcriptome atlas of murine endothelial cell.Cell. 2020; 180: 764-779Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]), and this is likely to expand our knowledge of the organ-specific molecular features of LECs in the future.Box 1Organ-specific structural specializations of lymphatic and 'lymphatic-like' vessels.Lymph nodesLN lymphatic vasculature consists of a complex network of sinuses that not only provide a structural barrier but also regulate immune cell trafficking and functions. The subcapsular sinus (SCS) underneath the capsule is the major site of cell entry into the LN parenchyma, whereas cortical and medullary sinuses channel fluid out of the LN and regulate lymphocyte functions and egress [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar]. Single-cell RNA sequencing of mouse and human LN LECs have revealed distinct LEC subsets that mirror the architecture and functional specialization of the vasculature [24.Arasa J. et al.Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation.J. Exp. Med. 2021; 218e20201413Crossref PubMed Scopus (0) Google Scholar,150.Xiang M. et al.A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature.Front. Cardiovasc. Med. 2020; 7: 52Crossref PubMed Google Scholar,151.Fujimoto N. et al.Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes.PLoS Biol. 2020; 18e3000704Crossref PubMed Scopus (15) Google Scholar]. These include Ackr4+ SCS floor LECs, the immune-active Ccl20+ SCS ceiling LECs, and the paracortical and medullary sinus subsets – Ptx3-LECs and Marco-LECs, respectively [150.Xiang M. et al.A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature.Front. Cardiovasc. Med. 2020; 7: 52Crossref PubMed Google Scholar].MeningesMeningeal lymphatics drain cerebrospinal fluid (CSF) and enable immune cell trafficking [152.Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar,153.Louveau A. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (1870) Google Scholar]. In contrast to most lymphatic vascular beds, these vessels form postnatally and require VEGF-C signaling for their maintenance [35.Antila S. et al.Development and plasticity of meningeal lymphatic vessels.J. Exp. Med. 2017; 214: 3645-3667Crossref PubMed Scopus (132) Google Scholar]. Although dorsal meningeal lymphatic vessels predominantly display zipper junctions (with the exception of the transverse sinuses), basal meningeal lymphatic vessels that appear as hotspots for CSF drainage display a typical capillary-like structure with button junctions and connect to collecting vessels equipped with lymphatic valves [148.Ahn J.H. et al.Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid.Nature. 2019; 572: 62-66Crossref PubMed Scopus (141) Google Scholar,152.Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar,154.Louveau A. et al.CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.Nat. Neurosci. 2018; 21: 1380-1391Crossref PubMed Scopus (206) Google Scholar].LungLymphatic vessels in the lung mature neonatally and start to drain interstitial fluid at late gestation, which increases compliance and is a prerequisite to allow lung inflation at birth [155.Jakus Z. et al.Lymphatic function is required prenatally for lung inflation at birth.J. Exp. Med. 2014; 211: 815-826Crossref PubMed Scopus (13) Google Scholar]. In contrast to other organs, collecting lymphatic vessels in the lung are devoid of SMCs [156.Reed H.O. et al.Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage.J. Clin. Invest. 2019; 129: 2514-2526Crossref PubMed Scopus (23) Google Scholar]. Respiratory movements and the resulting pressure changes are thought to aid lymph propulsion in the absence of intrinsic vessel contractions.LiverInitial lymphatics in the liver resemble lymphatic capillaries and are located in proximity to the portal vein within the portal triad [157.Tamburini B.A.J. et al.Chronic liver disease in humans causes expansion and differentiation of liver lymphatic endothelial cells.Front. Immunol. 2019; 10: 1036Crossref PubMed Scopus (13) Google Scholar]. Lymph fluid is generated by highly permeable fenestrated liver sinusoidal endothelial cells, and this is thought to account for the high protein content of the resulting lymph compared to other vascular beds. This fluid then flows from the hepatic interstitium via the space of Disse and the space of Mall towards the portal tract where it is drained by liver lymphatics [157.Tamburini B.A.J. et al.Chronic liver disease in humans causes expansion and differentiation of liver lymphatic endothelial cells.Front. Immunol. 2019; 10: 1036Crossref PubMed Scopus (13) Google Scholar].Hybrid vesselsLymphatic-like hybrid vessels that adopt partial LEC identity for their specialized functions in fluid clearance were recently described in the eye (Schlemm's canal) and kidney (ascending vasa recta) [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,158.Pawlak J.B. Caron K.M. Lymphatic programing and specialization in hybrid vessels.Front. Physiol. 2020; 11: 114Crossref PubMed Scopus (4) Google Scholar]. In addition, remodeling of placental spiral arteries is associated with acquisition of partial LEC identity, although these vessels do not possess a drainage function [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,158.Pawlak J.B. Caron K.M. Lymphatic programing and specialization in hybrid vessels.Front. Physiol. 2020; 11: 114Crossref PubMed Scopus (4) Google Scholar]. Lymph nodes LN lymphatic vasculature consists of a complex network of sinuses that not only provide a structural barrier but also regulate immune cell trafficking and functions. The subcapsular sinus (SCS) underneath the capsule is the major site of cell entry into the LN parenchyma, whereas cortical and medullary sinuses channel fluid out of the LN and regulate lymphocyte functions and egress [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar]. Single-cell RNA sequencing of mouse and human LN LECs have revealed distinct LEC subsets that mirror the architecture and functional specialization of the vasculature [24.Arasa J. et al.Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation.J. Exp. Med. 2021; 218e20201413Crossref PubMed Scopus (0) Google Scholar,150.Xiang M. et al.A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature.Front. Cardiovasc. Med. 2020; 7: 52Crossref PubMed Google Scholar,151.Fujimoto N. et al.Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes.PLoS Biol. 2020; 18e3000704Crossref PubMed Scopus (15) Google Scholar]. These include Ackr4+ SCS floor LECs, the immune-active Ccl20+ SCS ceiling LECs, and the paracortical and medullary sinus subsets – Ptx3-LECs and Marco-LECs, respectively [150.Xiang M. et al.A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature.Front. Cardiovasc. Med. 2020; 7: 52Crossref PubMed Google Scholar]. Meninges Meningeal lymphatics drain cerebrospinal fluid (CSF) and enable immune cell trafficking [152.Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar,153.Louveau A. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (1870) Google Scholar]. In contrast to most lymphatic vascular beds, these vessels form postnatally and require VEGF-C signaling for their maintenance [35.Antila S. et al.Development and plasticity of meningeal lymphatic vessels.J. Exp. Med. 2017; 214: 3645-3667Crossref PubMed Scopus (132) Google Scholar]. Although dorsal meningeal lymphatic vessels predominantly display zipper junctions (with the exception of the transverse sinuses), basal meningeal lymphatic vessels that appear as hotspots for CSF drainage display a typical capillary-like structure with button junctions and connect to collecting vessels equipped with lymphatic valves [148.Ahn J.H. et al.Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid.Nature. 2019; 572: 62-66Crossref PubMed Scopus (141) Google Scholar,152.Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar,154.Louveau A. et al.CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.Nat. Neurosci. 2018; 21: 1380-1391Crossref PubMed Scopus (206) Google Scholar]. Lung Lymphatic vessels in the lung mature neonatally and start to drain interstitial fluid at late gestation, which increases compliance and is a prerequisite to allow lung inflation at birth [155.Jakus Z. et al.Lymphatic function is required prenatally for lung inflation at birth.J. Exp. Med. 2014; 211: 815-826Crossref PubMed Scopus (13) Google Scholar]. In contrast to other organs, collecting lymphatic vessels in the lung are devoid of SMCs [156.Reed H.O. et al.Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage.J. Clin. Invest. 2019; 129: 2514-2526Crossref PubMed Scopus (23) Google Scholar]. Respiratory movements and the resulting pressure changes are thought to aid lymph propulsion in the absence of intrinsic vessel contractions. Liver Initial lymphatics in the liver resemble lymphatic capillaries and are located in proximity to the portal vein within the portal triad [157.Tamburini B.A.J. et al.Chronic liver disease in humans causes expansion and differentiation of liver lymphatic endothelial cells.Front. Immunol. 2019; 10: 1036Crossref PubMed Scopus (13) Google Scholar]. Lymph fluid is generated by highly permeable fenestrated liver sinusoidal endothelial cells, and this is thought to account for the high protein content of the resulting lymph compared to other vascular beds. This fluid then flows from the hepatic interstitium via the space of Disse and the space of Mall towards the portal tract where it is drained by liver lymphatics [157.Tamburini B.A.J. et al.Chronic liver disease in humans causes expansion and differentiation of liver lymphatic endothelial cells.Front. Immunol. 2019; 10: 1036Crossref PubMed Scopus (13) Google Scholar]. Hybrid vessels Lymphatic-like hybrid vessels that adopt partial LEC identity for their specialized functions in fluid clearance were recently described in the eye (Schlemm's canal) and kidney (ascending vasa recta) [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,158.Pawlak J.B. Caron K.M. Lymphatic programing and specialization in hybrid vessels.Front. Physiol. 2020; 11: 114Crossref PubMed Scopus (4) Google Scholar]. In addition, remodeling of placental spiral arteries is associated with acquisition of partial LEC identity, although these vessels do not possess a drainage function [1.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (46) Google Scholar,158.Pawlak J.B. Caron K.M. Lymphatic programing and specialization in hybrid vessels.Front. Physiol. 2020; 11: 114Crossref PubMed Scopus (4) Google Scholar]. The acquisition and maintenance of LEC identity requires the prospero homeobox 1 (PROX1) transcription factor [27.Escobedo N. Oliver G. Lymphangiogenesis: origin, specification, and cell fate determination.Annu. Rev. Cell Dev. Biol. 2016; 32: 677-691Crossref PubMed Scopus (48) Google Scholar], whereas the regulation of embryonic and postnatal lymphatic vessel growth is dependent on vascular endothelial growth factor C (VEGF-C) signaling via its main receptor VEGFR3 on LECs [28.Vaahtomeri K. et al.Lymphangiogenesis guidance by paracrine and pericellular factors.Genes Dev. 2017; 31: 1615-1634Crossref PubMed Scopus (58) Google Scholar]. VEGF-C also binds to the pan-endothelial VEGFR2 that serves as the receptor for the major angiogenic growth factor VEGF (also known as VEGF-A). The crucial importance of VEGF-C signaling for normal lymphatic development is exemplified by developmental lymphatic defects associated with mutations in genes encoding the core components of this pathway. Inactivating mutations in VEGFC or FLT4 (encoding VEGFR3), or in genes encoding modulators of VEGF-C activity (collagen and calcium binding EGF domains 1, CCBE1; and ADAM metallopeptidase with thrombospondin type 1 motif 3, ADAMTS3), cause lymphedema in patients (reviewed in [16.Martin-Almedina S. et al.Development and physiological functions of the lymphatic system – insights from genetic studies of lymphedema.Physiol. Rev. 2021; (Published online January 28, 2021. https://doi.org/10.1152/physrev.00006.2020)Crossref PubMed Google Scholar]). Interestingly, several other lymphangiogenic signaling mechanisms converge on the VEGF-C pathway. For example, a feedback loop between PROX1 and VEGF-C–VEGFR3 signaling controls LEC identity and lymphangiogenic activity [29.Srinivasan R.S. et al.The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors.Genes Dev. 2014; 28: 2175-2187Crossref PubMed Scopus (75) Google Scholar, 30.Cha B. et al.YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling.Development. 2020; 147dev195453Crossref PubMed Scopus (8) Google Scholar, 31.Koltowska K. et al.Vegfc regulates bipotential precursor division and prox1 expression to promote lymphatic identity in zebrafish.Cell Rep. 2015; 13: 1828-1841Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 32.Ma W. et al.Mitochondrial respiration controls the Prox1–Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance.Sci. Adv. 2021; 7eabe7359Crossref PubMed Scopus (1) Google Scholar], whereas the lymphatic valve regulators GATA2 and ephrin B2 regulate VEGFR3 expression and signaling, respectively [33.Wang Y. et al.Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.Nature. 2010; 465: 483-486Crossref PubMed Scopus (702) Google Scholar,34.Frye M. et al.Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program.Nat. Commun. 2018; 9: 1511Crossref PubMed Scopus (52) Google Scholar]. Despite its crucial role in lymphangiogenesis, VEGF-C appears to be dispensable for homeostatic maintenance of functional lymphatic vessels in most organs, with the exception of the intestine and meninges [35.Antila S. et al.Development and plasticity of meningeal lymphatic vessels.J. Exp. Med. 2017; 214: 3645-3667Crossref PubMed Scopus (132) Google Scholar,36.Nurmi H. et al.VEGF-C is" @default.
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• W3186164565 date "2021-10-01" @default.
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• W3186164565 title "Homeostatic maintenance of the lymphatic vasculature" @default.
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