Capillary sprout endothelial cells exhibit a CD36 low phenotype: regulation by shear stress and vascular endothelial growth factor-induced mechanism for attenuating anti-proliferative thrombospondin-1 signaling.
Endothelial cells acquire distinctive molecular signatures in their transformation to an angiogenic phenotype that are indicative of changes in cell behavior and function. Using a rat mesentery model of inflammation-induced angiogenesis and a panel of known endothelial markers (CD31, VE-cadherin, BS-I lectin), we identified a capillary sprout-specific endothelial phenotype that is characterized by the marked down-regulation of CD36, a receptor for the anti-angiogenic molecule thrombospondin-1 (TSP-1). TSP-1/CD36 interactions were shown to regulate angiogenesis in this model as application of TSP-1 inhibited angiogenesis and blockade of both TSP-1 and CD36 accelerated angiogenesis. Vascular endothelial growth factor, which was up-regulated in the in vivo model, elicited a dose- and time-dependent down-regulation of CD36 (ie, to a CD36 low phenotype) in cultured human umbilical vein endothelial cells. Human umbilical vein endothelial cells that had been conditioned to a CD36 low phenotype with VEGF were found to be refractory to anti-proliferative TSP-1 signaling via a CD36-dependent mechanism. The loss of exposure to wall shear stress, which occurs in vivo when previously quiescent cells begin to sprout, also generated a CD36 low phenotype. Ultimately, our results identified the regulation of endothelial cell CD36 expression as a novel mechanism through which VEGF stimulates and sustains capillary sprouting in the presence of TSP-1. Additionally, CD36 was shown to function as a potential molecular linkage through which wall shear stress may regulate both microvessel sprouting and quiescence.
Anderson
Christopher R
CR
Department of Biomedical Engineering and the Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Hastings
Nicole E
NE
Blackman
Brett R
BR
Price
Richard J
RJ
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D019700:Thrombospondin 1 / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology
D018955:CD36 Antigens; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A
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