Angiotensin II stimulates migration of retinal microvascular pericytes: involvement of TGF-beta and PDGF-BB.
We studied the promigratory effect of angiotensin II (ANG II) on cultured bovine retinal microvascular pericytes. ANG II stimulated migration of pericytes by 86% at 10(-8) M, but this effect was lost at 10(-4) M. Migratory responses were inhibited by the ANG II type 1 (AT(1)) receptor antagonist losartan but not by PD-123319, an AT(2) antagonist. Addition of PD-123319 to the 10(-4) M ANG II dose restored migratory responses. The promigratory effect of ANG II (10(-7) M) was reduced by 59% in absence of gradient. Although ANG II augmented the latent matrix metalloproteinase-2 (MMP-2) activity of the pericyte by 35%, it also doubled tissue inhibitors of MMPs. ANG II-induced migration was not altered by a broad-spectrum MMP inhibitor (GM6001); it was inhibited by ~50% by antibodies against transforming growth factor (TGF)-beta(1/2/3) and was abolished by antibodies against platelet-derived growth factor (PDGF)-BB. We conclude that ANG II induces chemotactic responses on retinal microvascular pericytes acting through the AT(1) receptor. This effect is opposed by the AT(2) receptor. ANG II-induced chemotaxis is mediated by PDGF-BB and involves TGF-beta, but it is independent of MMP activity. It is also independent of vascular endothelial growth factor (VEGF) because VEGF did not stimulate pericyte migration. ANG II can contribute to the regulation of retinal neovascularization by stimulating pericyte migration.
Nadal
Jose A
JA
Eye Care Services Research, Henry Ford Health System, Detroit, Michigan 48202-3450, USA.
Scicli
G M
GM
Carbini
L A
LA
Scicli
A Guillermo
AG
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077214:Becaplermin; D002417:Cattle; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008833:Microcirculation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000276:immunology / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000502:physiology; D012160:Retina / Q000166:cytology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000906:Antibodies; D000925:Anticoagulants; D000959:Antihypertensive Agents; D004151:Dipeptides; D016228:Endothelial Growth Factors; D007093:Imidazoles; D008222:Lymphokines; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010982:Platelet-Derived Growth Factor; D011480:Protease Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; C073402:PD 123319; D000077214:Becaplermin; D020778:Matrix Metalloproteinase 2; D019808:Losartan