Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes

Abstract

Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxiainducible factor 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2α-deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2α-dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2α-dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2α in ECs. These results indicate that HIF-1α and HIF-2α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

“…4 I and J) indicated that vessel maturation is inhibited in T3691-218 tumors. This effect of miR-218 on tumor angiogenesis is consistent with the impact of reduced HIF2α activity in other tumor model systems (42,43). Cheng et al (44) recently demonstrated that GSCs can transdifferentiate into pericytes, and delineating a role for an miR-218-RTK-HIF2α signaling axis in this process is warranted in the future.…”

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…The VE-cadherin mouse line has been widely used to investigate endothelial-specific gene deletion in different experimental settings, although Cre expression in this mouse line exists to a lesser extent in hematopoietic cells. [53][54][55] In conjunction with our studies using Adora2b reporter mice showing almost exclusive expression of the Adora2b in the vasculature of diabetic kidneys, we believe that the most likely explanation of our findings is vascular Adora2b signaling as a mediator of kidney protection during diabetic nephropathy.…”

Macrophages Aggravate Hypoxia-Induced Cardiac Microvascular Endothelial Cell Injury via Peroxynitrite: Protection by Tongxinluo

“…HIF-1a and HIF-2a are induced by hypoxia, which can drive VEGF expression, resulting in angiogenesis (Skuli et al, 2012;Kapitsinou et al, 2014;Oh et al, 2015). Contrary to iNOS, eNOS plays constitutive roles in physiological vasodilatation and ECE-1 is also an important regulator of vascular tone Robinson et al, 2014).…”

“…Mammalian HIFs function as heterodimers composed of either HIF-1a or HIF-2a bound to HIF-1b. HIF-1a appears to be ubiquitously expressed, whereas HIF-2a is more restricted to vascular endothelial cells (Skuli et al, 2012;Kapitsinou et al, 2014). HIFs control a series of genes that help in adaptation to hypoxia.…”