Endoglin Regulates the Activation and Quiescence of Endothelium by Participating in Canonical and Non-Canonical TGF-β Signaling Pathways

Abstract

SummaryEndoglin (Eng) is an auxiliary receptor for transforming growth factor-b (TGFb), with important roles in vascular function. TGFb regulates angiogenesis through balancing the pro-proliferative and pro-differentiation signaling pathways of endothelial cells (EC). However, the contribution of endoglin to these TGFb activities, and more specifically modulation of EC phenotype, remains elusive. Mutations in endoglin cause hereditary hemorrhagic telangiectasia-1 in humans. The Eng+/2 mice are viable and exhibit some of the vascular defects seen in humans with endoglin haploinsufficiency. In the present study we show that haploinsufficiency of endoglin results in attenuation of retinal neovascularization during oxygen-induced ischemic retinopathy. Although the importance of endoglin expression in angiogenesis and vascular development has been demonstrated, the underlying mechanisms remain obscure. To gain detailed insight into the cell autonomous regulatory mechanisms that affect angiogenic properties of EC, we prepared retinal EC from Eng+/+ and Eng+/2 Immorto mice. The Eng+/2 EC were more adherent, less migratory, and failed to undergo capillary morphogenesis. Aortic sprouting angiogenesis was similarly attenuated in aortas from Eng+/2 mice. In addition, Eng+/2 EC expressed increased levels of VEGF but reduced expression of endothelial NO synthase and NO production. Mechanistically, these changes were consistent with sustained activation of mitogen-activated protein kinase (MAPK) pathways, and aberrant Smad-dependent signaling pathways in Eng+/2 EC. Taken together, our results underscore the importance of endoglin in both canonical and non-canonical TGFb signaling pathways modulating both the activation and quiescence of the endothelium during angiogenesis.

The role of endoglin in post-ischemic revascularization

“…As described above, reduced retinal neovascularization has recently been reported in Eng +/-mice after OIR due to an impaired angiogenic response of ECs [18]. However, endoglin can function as a protective factor against endothelial apoptosis because endoglin inhibition enhances hypoxia and TGF-β-induced endothelial apoptosis [155].…”

“…In a rat myoblast model, TGF-β showed an antiproliferative effect both at low and high doses, and the effect at lower doses was rescued by overexpression of endoglin [139]. Conversely, low doses of TGF-β have shown an endoglinmediated antiproliferative effect in ECs isolated from the retina, as this effect was abrogated in ECs from Eng +/-retinas [18]. These divergent results could again be explained based on the different types of cells used and their different origins.…”

“…Moreover, endoglin is also highly expressed in blood vessels upon vascular injury in humans and mice [115], after oxygen-induced angiogenesis in the retina [17,18] and during pathological angiogenesis in chronic colitis [116].…”

“…These two effects explain the delayed blood flow recovery after induction of hind limb ischemia [22]. Retinal neovascularization in Eng +/-mice after oxygeninduced ischemic retinopathy (OIR) revealed markedly impaired angiogenesis in the retina, with little or no angiogenic tuft formation [18]. However, a larger number of proliferative cells have been reported within the vasculature of normal retinas from Eng +/-mice at different stages of development, as compared with wild type mice.…”

“…Endoglin expression is enhanced in endothelium during active angiogenesis, both in non-tumor and tumor tissues [15,16], and endoglin expression specifically rises at the angiogenic edge where vessel sprouting occurs [17]. A lack of endoglin or defective endoglin function results in impaired angiogenesis, revascularization and tumor growth [18][19][20][21][22]. Moreover, endoglin is used as a biomarker for a poor prognosis in several cancers [23,24], and endoglin-neutralizing antibodies have demonstrated antitumor angiogenesis properties, as recently reviewed [25,26].…”