Critical role of endothelial regulator of G protein signaling 5 in postnatal angiogenesis

Regulator of G protein signaling 5 (RGS5) modulates G-protein coupled receptor (GPCR) signaling and is markedly upregulated in angiogenesis. However, its function in endothelial cells and its role in mediating postnatal angiogenesis remain unclear. The purpose of this study is to define the role of endothelial RGS5 in regulating VEGF signaling and angiogenesis.

In a hindlimb ischemia model, we found impaired postnatal angiogenesis, reduced perfusion recovery, and increased rates of auto-amputation in mice with either global or endothelial-specific deletion of Rgs5. Rgs5 deficiency in ECs led to reduced VEGFR2 phosphorylation at Tyr¹¹⁷⁵ and its downstream signaling pathways. This was accompanied by increased activity of the tyrosine phosphatase, SHP-1, which dephosphorylates and inactivates VEGFR2. In vitro, Rgs5-deficient ECs exhibited diminished migration, increased apoptosis, and reduced viability in response to VEGF stimulation. These findings indicate that RGS5 is essential for maintaining VEGF-mediated angiogenic signaling through inhibition of SHP-1 activity.

Endothelial RGS5 is a critical regulator of VEGF signaling and postnatal angiogenesis. By attenuating SHP-1-mediated dephosphorylation of VEGFR2, RGS5 preserves VEGF signaling and angiogenesis. Targeting the RGS5-SHP-1 axis may be a useful therapeutic strategy for improving angiogenesis in response to ischemia.