+1 Recommend
1 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Lymphatic network in atherosclerosis: the underestimated path


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          The lymphatic system is a key component of tissue fluid homeostasis. In contrast to the closed and high-pressure blood vascular system, the lymphatic vascular system transports lymph in an open and low-pressure network. A prerequisite player in the transport of immune cells and cholesterol metabolism, it has been understudied until recently. Whereas defects in lymph circulation are mostly associated with pathologies such as congenital or acquired lymphedema, emerging significant developments are unraveling the role of lymphatic vessels in other pathological settings. In the last decade, discoveries of underlying genes responsible for developmental and postnatal lymphatic growth, combined with state-of-the-art lymphatic function imaging and quantification techniques, have matched the growing interest in understanding the role of the lymphatic system in atherosclerosis. With a historical perspective, this review highlights the current knowledge regarding interaction between the lymphatic vascular tree and atherosclerosis, with an emphasis on the physiological mechanisms of this multifaceted system throughout disease onset and progression.


          The blood and lymphatic vascular systems are parallel but interdependent networks. The lymphatic system governs the transport of superfluous interstitial fluids from peripheral tissues to the blood circulation, maintaining fluid balance throughout the body. Defects in lymphatic function have been broadly associated with pathologies such as congenital or acquired lymphedema. Although longstanding observations suggested that the lymphatic vasculature could be central in the development of chronic inflammatory diseases, recent publications specifically point out its potential implication in atherosclerosis. In this review, we highlight the current knowledge unraveling the interaction between the lymphatic network and atherosclerosis, with an emphasis on the physiological mechanisms of this intricate system.

          Most cited references63

          • Record: found
          • Abstract: found
          • Article: not found

          Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function.

          Major features of the transcellular signaling mechanism responsible for endothelium-dependent regulation of vascular smooth muscle tone are unresolved. We identified local calcium (Ca(2+)) signals ("sparklets") in the vascular endothelium of resistance arteries that represent Ca(2+) influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a four-channel cluster was cooperative, with activation of as few as three channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)- and small (SK)-conductance, Ca(2+)-sensitive potassium (K(+)) channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. These results support the concept that Ca(2+) influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high Ca(2+) sensitivity of IK and SK channels to cause vasodilation.
            • Record: found
            • Abstract: found
            • Article: not found

            Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor.

            Lymphatic vessels are essential for fluid homeostasis, immune surveillance and fat adsorption, and also serve as a major route for tumor metastasis in many types of cancer. We found that isolated human primary lymphatic and blood vascular endothelial cells (LECs and BECs, respectively) show interesting differences in gene expression relevant for their distinct functions in vivo. Although these phenotypes are stable in vitro and in vivo, overexpression of the homeobox transcription factor Prox-1 in the BECs was capable of inducing LEC-specific gene transcription in the BECs, and, surprisingly, Prox-1 suppressed the expression of approximately 40% of the BEC-specific genes. Prox-1 did not have global effects on the expression of LEC-specific genes in other cell types, except that it up-regulated cyclin E1 and E2 mRNAs and activated the cyclin e promoter in various cell types. These data suggest that Prox-1 acts as a cell proliferation inducer and a fate determination factor for the LECs. Furthermore, the data provide insights into the phenotypic diversity of endothelial cells and into the possibility of transcriptional reprogramming of differentiated endothelial cells.
              • Record: found
              • Abstract: found
              • Article: not found

              Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice.

              Reverse cholesterol transport (RCT) refers to the mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves peripheral tissues to reach plasma. We first used 2 models of disrupted lymphatic drainage from skin--1 surgical and the other genetic--to quantitatively track RCT following injection of [3H]-cholesterol-loaded macrophages upstream of blocked or absent lymphatic vessels. Macrophage RCT was markedly impaired in both models, even at sites with a leaky vasculature. Inhibited RCT was downstream of cholesterol efflux from macrophages, since macrophage efflux of a fluorescent cholesterol analog (BODIPY-cholesterol) was not altered by impaired lymphatic drainage. We next addressed whether RCT was mediated by lymphatic vessels from the aortic wall by loading the aortae of donor atherosclerotic Apoe-deficient mice with [2H]6-labeled cholesterol and surgically transplanting these aortae into recipient Apoe-deficient mice that were treated with anti-VEGFR3 antibody to block lymphatic regrowth or with control antibody to allow such regrowth. [2H]-Cholesterol was retained in aortae of anti-VEGFR3-treated mice. Thus, the lymphatic vessel route is critical for RCT from multiple tissues, including the aortic wall. These results suggest that supporting lymphatic transport function may facilitate cholesterol clearance in therapies aimed at reversing atherosclerosis.

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                November 2015
                01 November 2015
                : 1
                : 4
                : FSO61
                [1 ]Montreal Heart Institute, Research Center, Montreal, QC, Canada
                [2 ]Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
                Author notes
                *Author for correspondence: catherine.martel@ 123456icm-mhi.org
                © Catherine Martel

                This work is licensed under a Creative Commons Attribution 4.0 License


                atherosclerosis,lymphatic endothelium,lymphatic smooth muscle cells,lymphatic vessels


                Comment on this article