Angiotensin II stimulates migration of retinal microvascular pericytes: involvement of TGF-β and PDGF-BB

Abstract

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.

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

“…A previous in vitro study has reported PD123319 to not attenuate ANG II-stimulated retinal pericyte migration. 12 In the present study, we found in both sham and untreated ROP rats, that both AT1 and AT2 receptors were localized not only to blood vessels but also to the ILM and nuclei in the INL, which presumably represent macroglial Muller cells. Importantly, Muller cells are associated with retinal blood vessels 47 and are sites of VEGF and VEGF-R2 expression.…”

“…[1][2][3] There is accumulating evidence that angiotensin II (ANG II), the effector peptide of the renin-angiotensin system (RAS), is a key pathophysiological factor in a number of retinal vascular disorders including ROP and PDR. 4 -7 In addition to its well characterized hemodynamic actions, ANG II is also a growth factor, stimulating endothelial and smooth muscle cell proliferation, 8 -10 pericyte migration, 11,12 and smooth muscle cell hypertrophy. 13 The actions of ANG II are largely mediated by two receptors; angiotensin type 1 (AT1) and angiotensin type 2 (AT2).…”

Differential mechanisms of angiotensin II and PDGF-BB on migration and proliferation of coronary artery smooth muscle cells

“…In contrast, selective inhibition of each pathway displayed similar effects on NADPH oxidase, CuZn-SOD and NOS activities. The similarities in these responses can in part be explained by the well-documented presence of a cross-talk between G-protein coupled AT 1 R and the PDGF receptor tyrosine kinase in vascular SMCs and thus the ability of Ang II to elicit responses unique to growth factor stimulation [15,16,37].…”

“…Furthermore, recent data have implicated PDGF-BB in Ang II-induced chemotaxis and revealed the ability of Ang II to activate PDGF- receptor [15,16]. Taken these close functional interactions into account, the present study examined whether mechanistic dis/similarities exist between these atherogens to trigger vascular pathologies.…”

In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy

“…22 It is possible that VEGF signaling is not completely blocked by endostatin. However, other factors, like IGF-1, TGF B and PDGF, 23,24 contribute to retinal neovascularization in ischemic retinopathies and could be responsible for residual angiogenesis. Indeed, Ozaki et al 25 have totally inhibited retinal neovascularization in the same mouse model of retinal neovascularization by using a kinase inhibitor that targets VEGF and PDGF receptors.…”