A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A
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- 作者：Antony M. Latham ; Adam F. Odell ; Nadeem A. Mughal ; Theo Issitt ; Clare Ulyatt ; John H. Walker ; Shervanthi Homer-Vanniasinkam ; Sreenivasan Ponnambalam
- 关键词：5-FU ; 5-fluorouracil ; bFGF ; basic fibroblast growth factor ; ECD ; extracellular domain ; ECM ; extracellular matrix ; ERK1/2 ; extracellular signal-regulated kinases 1 and 2 ; HUVEC ; human umbilical vein endothelial cells ; MAPKAPK2 ; mitogen-activated protein ki
- 刊名：Experimental Cell Research
- 出版年：2012
- 出版时间：1 November, 2012
- 年：2012
- 卷：318
- 期：18
- 页码：2297-2311
- 全文大小：1777 K
文摘
Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states.