Potential Regulatory Roles of GRK2 in Endothelial Cell Activity and Pathological Angiogenesis

Abstract

G protein-coupled receptor (GPCR) kinase 2 (GRK2) is an integrative node in many signaling network cascades. Emerging evidence indicates that GRK2 can interact with a large number of GPCRs and non-GPCR substrates in both kinase-dependent and -independent modes. Some of these pathways are associated with endothelial cell (EC) activity. The active state of ECs is a pivotal factor in angiogenesis. The occurrence and development of some inflammation-related diseases are accompanied by pathological angiogenesis, but there remains a lack of effective targeted treatments. Alterations in the expression and/or localization of GRK2 have been identified in several types of diseases and have been demonstrated to regulate the angiogenesis process in these diseases. GRK2 as a target may be a promising candidate for anti-angiogenesis therapy.

Keywords: GPCRs; GRK2; activity; angiogenesis; endothelial cells.

Figure 1

Schematic of GRK2 signaling pathways regulating endothelial cell activity, angiogenesis, and related disease progression. On the one hand, GPCRs and non-GPCRs binding with agonists can activate Smad2/3 signal and PI3K/AKT signaling pathway, resulting in downregulation of GRK2 expression level. Reduced GRK2 expression level reduces GPCR desensitization and the inhibition of non-GPCRs. On the other hand, PGE2 activates the EP4/AC/cAMP/PKA pathway, which mediates GRK2 translocation to the cell membrane, resulting in the reduction of ERK inhibition. In different disease conditions, the decreased GRK2 expression or the increased GRK2 translocation may improve the activity of endothelial cells, and thus promote angiogenesis and disease progression. VEGF, vascular endothelial growth factor; TGFβ, transforming growth factor β; VEGFR2, vascular endothelial growth factor receptor 2; ALK5, TGF-β type I receptor ALK5 (activin receptor-like kinase 5); S1P, sphingosine 1 phosphate; S1PR1, sphingosine 1 phosphate receptor 1; β₂AR, β₂-adrenergic receptor; CXCR2, chemokine (C-X-C motif) receptor 2; PGE2, prostaglandin E2; EP4, prostaglandin E2 receptor 4; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; cAMP, cyclic adenosine monophosphate; PKA, Protein Kinase A; ERK, extracellular regulated protein kinases; memb, membrane; cyt, cytoplasm.