title: Angiotensin II modulates VEGF-driven angiogenesis by opposing effects of type 1 and type 2 receptor stimulation in the microvascular endothelium.
abstract: Vascular endothelial growth factor (VEGF) is a main stimulator of pathological vessel formation. Nevertheless, increasing evidence suggests that Angiotensin II (Ang II) can play an augmentory role in this process. We thus analyzed the contribution of the two Ang II receptor types, AT(1)R and AT(2)R, in a mouse model of VEGF-driven angiogenesis, i.e. oxygen-induced proliferative retinopathy. Application of the AT(1)R antagonist telmisartan but not the AT(2)R antagonist PD123,319 largely attenuated the pathological response. A direct effect of Ang II on endothelial cells (EC) was analyzed by assessing angiogenic responses in primary bovine retinal and immortalized rat microvascular EC. Selective stimulation of the AT(1)R by Ang II in the presence of PD123,319 revealed a pro-angiogenic activity which further increased VEGF-driven EC sprouting and migration. In contrast, selective stimulation of the AT(2)R by either CGP42112A or Ang II in the presence of telmisartan inhibited the VEGF-driven angiogenic response. Using specific inhibitors (pertussis toxin, RGS proteins, kinase inhibitors) we identified G(12/13) and G(i) dependent signaling pathways as the mediators of the AT(1)R-induced angiogenesis and the AT(2)R-induced inhibition, respectively. As AT(1)R and AT(2)R stimulation displays opposing effects on the activity of the monomeric GTPase RhoA and pro-angiogenic responses to Ang II and VEGF requires activation of Rho-dependent kinase (ROCK), we conclude that the opposing effects of the Ang II receptors on VEGF-driven angiogenesis converge on the regulation of activity of RhoA-ROCK-dependent EC migration.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Carbajo-Lozoya
authors.forename: Susanne
authors.initials: S
authors.lastname: Lutz
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Feng
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012160:Retina / Q000473:pathology* / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D044365:GTP-Binding Protein alpha Subunits, G12-G13