Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) ‐dependent signaling

Abstract

Angiogenesis and vascular cell proliferation are pivotal in physiological and pathological processes including atherogenesis, restenosis, wound healing, and cancer development. Here we show that mammalian target of rapamycin (mTOR) signaling plays a key role in hypoxia-triggered smooth muscle and endothelial proliferation and angiogenesis in vitro. Hypoxia significantly increased DNA synthesis and proliferative responses to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) in rat and human smooth muscle and endothelial cells. In an in vitro 3-dimensional model of angiogenesis, hypoxia increased PDGF- and FGF-stimulated sprout formation from rat and mouse aortas. Hypoxia did not modulate PDGF receptor mRNA, protein, or phosphorylation. PI3K activity was essential for cell proliferation under normoxic and hypoxic conditions. Activities of PI3K-downstream target PKB under hypoxia and normoxia were comparable. However, mTOR inhibition by rapamycin specifically abrogated hypoxia-mediated amplification of proliferation and angiogenesis, but was without effect on proliferation under normoxia. Accordingly, hypoxia-mediated amplification of proliferation was further augmented in mTOR-overexpressing endothelial cells. Thus, signaling via mTOR may represent a novel mechanism whereby hypoxia augments mitogen-stimulated vascular cell proliferation and angiogenesis.

Combination treatment significantly enhances the efficacy of antitumor therapy by preferentially targeting angiogenesis

“…19 The PI3K/Akt pathway is also used by other growth factors like basic fibroblast growth factor and platelet-derived growth factor to mediate angiogenesis and EC protection. 28 We therefore hypothesize that treatment with PI3 K inhibitor prior to irradiation may be a useful strategy to overcome resistance in the ECs lining the tumor blood vessels and thereby enhance the effectiveness of g-radiation and chemotherapy.…”

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…In this model, elevated levels of PHDs represents an adaptive step to match the stabilized HIFs and, thus, limit the effect of the mTOR pathway on HIF-1 [53]. The involvement of the mTOR in the regulation of HIF-1 was first suggested by independent studies of the oncogene-related activation of VEGF [54][55][56][57][58]. Although mTOR is believed to act as a hub for various signaling pathways, the PKB/Akt pathway was found to be the dominant upstream regulator of the mTOR-mediated HIF-1 activity in hypoxia [59][60][61].…”

Angiogenic Effects of Interleukin 8 (CXCL8) in Human Intestinal Microvascular Endothelial Cells Are Mediated by CXCR2

“…Wortmannin, a multicyclic fungal metabolite and a selective inhibitor of PI3K, is a potent inhibitor of angiogenesis in vivo (62) and EC chemotaxis (61). In turn, the intracellular lipid kinase PI3K is now appreciated as a critical mediator of angiogenesis through its downstream targets PKB (63) and Akt, a serine/ threonine protein kinase (64), as overexpression of the catalytic subunit of PI3K as well as of constitutively active Akt has revealed increased in vivo angiogenesis in the chicken chorioallantoic membrane assay (65). Activation of ERK 1/2 by chemokines seems to be a signaling event downstream of PI3K, because phosphorylation of ERK 1/2 in response to several chemokines can be inhibited by PI3K inhibitors (58,66).…”