Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival

Abstract

Pericytes have been suggested to play a role in regulation of vessel stability; one mechanism for this stabilization may be via pericyte-derived vascular endothelial growth factor (VEGF). To test the hypothesis that differentiation of mesenchymal cells to pericytes/smooth muscle cells (SMC) is accompanied by VEGF expression, we used endothelial cell (EC) and mesenchymal cell cocultures to model cell-cell interactions that occur during vessel development. Coculture of EC and 10T1/2 cells, multipotent mesenchymal cells, led to induction of VEGF expression by 10T1/2 cells. Increased VEGF expression was dependent on contact between EC-10T1/2 and was mediated by transforming growth factorbeta (TGFbeta). A majority of VEGF produced in coculture was cell- and/or matrix-associated. Treatment of cells with high salt, protamine, heparin, or suramin released significant VEGF, suggesting that heparan sulfate proteoglycan might be sequestering some of the VEGF. Inhibition of VEGF in cocultures led to a 75% increase in EC apoptosis, indicating that EC survival in cocultures is dependent on 10T1/2-derived VEGF. VEGF gene expression in developing retinal vasculature was observed in pericytes contacting newly formed microvessels. Our observations indicate that differentiated pericytes produce VEGF that may act in a juxtacrine/paracrine manner as a survival and/or stabilizing factor for EC in microvessels.

Adrenomedullin/Cyclic AMP Pathway Induces Notch Activation and Differentiation of Arterial Endothelial Cells From Vascular Progenitors

“…5,6 On the other hand, their ligands, VEGF, Jagged1, and AM, are expressed in MCs. 8,41,42 Dll4 and AM are also expressed in ECs. We confirmed AM mRNA expression in ES cell-derived ECs and MCs, and RAMP-2 and CRLR mRNA in ECs by reverse-transcription polymerase chain reaction analysis.…”

Vascular endothelial growth factor in eye disease

“…The differentiation of immature mesenchymal cells into pericytes upon contact with endothelial cells is associated with increased VEGF expression. VEGF produced by differentiated pericytes plays an important role in pericyte spreading over endothelial cells in both normoxic and hyperoxic conditions (Darland and Massingham, 2003;Benjamin and Hemo, 1998). Other factors, including PDGF-β and TGF-β secreted by endothelial cells, and the angiopoietins also play a role in pericyte recruitment (Lindahl et al, 1997;Hirschi and D'Amore, 1996;Suri et al, 1996).…”

Bosentan protects the spinal cord from ischemia reperfusion injury in rats through vascular endothelial growth factor receptors

“…VEGF is important for endothelial cell proliferation and survival, which are mediated via FLK-1. 24 Enhanced survival of endothelial cells could promote angiogenesis, reduce capillary breakdown and bleeding and preserve adequate microcirculation and perfusion, thereby contributing to increased neuronal survival. 23 In addition, inhibition of FLT-1 reduced brain edema after cerebral ischemia in rats, which may be associated with the protection of blood-brain barrier permeability and induction of macrophage/monocyte infiltration.…”