Hypoxia upregulates integrin gene expression in microvascular endothelial cells and promotes their migration and capillary‐like tube formation

Abstract

Tissue hypoxia affects gene expression through the hypoxia-inducible transcription factors, HIF-1 and HIF-2, in both physiological and pathological angiogenesis. Angiogenesis is a complex response of endothelial cells integrating cell proliferation, migration, tube formation, and their interaction with the extracellular matrix through integrin receptors. In this report, we studied the effect of hypoxia on the angiogenic functions of human microvascular endothelial cells (HMEC-1) as well as on expression of the angiogenic integrins α β , α β , and α β . Exposure of HMEC-1 to hypoxia (1% O ) or to DMOG, a prolyl-4-hydroxylase inhibitor, caused significant reduction to their proliferation rate, whereas their migration ability toward laminin-1 or collagen IV and capillary-like tube formation were significantly enhanced. In addition, α , β , β , and β integrins expression was increased under hypoxia in HMEC-1, while α integrin was not affected. Both HIF-1 and HIF-2 protein expression and transcriptional activity were induced under hypoxia in HMEC-1. The knockdown of either HIF-1α or HIF-2α inhibited integrin β hypoxic stimulation, suggesting a HIF-dependent induction of β integrin in HMEC-1. Taken together, our results indicate that hypoxia transcriptionally up-regulates angiogenic integrins in microvascular endothelial cells along with promoting migration and tube formation of HMEC-1.

Chronic Hypoxia‐Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL‐6/JAK2/STAT3/MMP‐9 Pathway

“…Additionally, previous studies have shown that vascular endothelial cells are produced under hypoxic conditions, which enhance microvessel proliferation. Consistent with these findings, we observed that, under hypoxia, the MVD increased because the vascular endothelial cells are produced [46][47][48][49][50].…”

The role of microenvironment in tumor angiogenesis

“…Hypoxia has been shown to induce the expression of MMP2 and MMP9, which are important molecules for tumor cell invasion and metastasis [23][24][25]. In addition, hypoxia-induced integrin β3 expression can affect endothelial cell tube formation [26].…”

HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes

“…To induce HIF1α production, adipocytes were cultured under hypoxia (2% O 2 ) plus the HIF1α stabilizer, (DMOG, 500 µM) as previously described [19] [20]. We tested three different concentrations of CAY10585 (10, 20, and 30µM), which decreased the nuclear fraction of HIF1α protein, by 55%, 74%, and 90%, respectively ( Figure 1D).…”