Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

Abstract

Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von HippelLindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

“…Of note, oxLDL proangiogenic effects are partially lost upon HIF-1α inhibition (121). The notion that myeloid HIF-1α can promote angiogenesis through VEGF upregulation is demonstrated in other studies as well (123). Macrophages can also contribute to pathogenesis by secreting proteoglycans such as versican, which modulate lipoprotein retention and the activity of enzymes, cytokines, and other growth factors in atherosclerotic lesions.…”

CDKN2B Regulates TGF β Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels

“…Subsequent immunohistochemistry, gene expression, vessel density, vascular permeability and ambulatory impairment studies were performed, as described in the Supplemental materials 15, 16 . All studies were approved by the Stanford University Administrative Panel on Laboratory Animal Care.…”

Molecular Controls of Arterial Morphogenesis

“…SMC proliferation entails a switch in SMC phenotype from contractile to proliferative that can be activated directly by mechanical stresses as well as by nitric oxide. The critical role played by NO is demonstrated by a markedly reduced arteriogenesis and vessel rarefication in eNOS null mice 83, 84 albeit the latter may also be due to the regulatory role of NO in regulation of angiopoietin-2 release from endothelial cells 85 . At the same time, dysregulation of G protein signaling in SMC as, for example, seen with a knockout of RGS5 also affects arteriogenesis 63 .…”

“…90 On the other hand, macrophages with reduced VEGF-A expression demonstrate defective adult arteriogenesis, 91 while expansion of macrophage population due to, for example, PHD2 haploinsufficiency, significantly increases developmental and adult arteriogenesis 92 . Similarly, activating macrophage HIF-1α expression promotes while suppressing it inhibits, adult arteriogenesis 85 .…”