Regulation of Angiogenesis in Choroidal Neovascularization of Age Related Macular Degeneration by Endogenous Angioinhibitors

Gunda, Venugopal; Sudhakar, Yakkanti Akul

doi:10.5772/26807

Cited by 2 publications

(2 citation statements)

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“…37 Regulation of angiogenic responses in ECs by NC1 domains of type IV collagen and EDPs are facilitated through the binding of these angiogenic regulators to the cell surface receptors. 17,21,28,[38][39][40] Such binding leads to integrin receptor activation and downstream kinase activation promoting EC migration. 15,41 Antiangiogenic effects of other NC1 domains of type IV collagen were shown earlier to be elicited through the inhibition of FAK-mediated kinase signaling.…”

Section: Discussionmentioning

confidence: 99%

“…2,5 In contrast, degradation of type IV collagen leads to the release of NC1 domains with antiangiogenic properties, which inhibit pathologic angiogenesis. 14,[25][26][27][28] Our study was done to evaluate the net effects of a6(IV)NC1 domain and EDPs in regulation of MCECs angiogenic patterns in vitro. Angiogenic effects of different EDPs in CNV were studied previously using cultured CECs of monkey and human origin.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Elastin Peptide-Mediated Angiogenic Signaling Mechanism(s) in Choroidal Endothelial Cells by the α6(IV)NC1 Collagen Fragment

Gunda

Verma

Sudhakar

2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Gunda V, Verma RK, Sudhakar YA. Inhibition of elastin peptidemediated angiogenic signaling mechanism(s) in choroidal endothelial cells by the a6(IV)NC1 collagen fragment. Invest Ophthalmol Vis Sci. 2013;54:7828-7835. DOI:10.1167/ iovs.12-10870 PURPOSE. The inhibitory effects and mechanism(s) of type IV collagen a-6 chain-derived noncollagenous domain (a6[IV]NC1 or hexastatin) on elastin-derived peptide (EDP)-activated choroidal endothelial cell migration, kinase signaling, and membrane type 1 metalloproteinase (MT1-MMP) activation are explored. METHODS.Mouse choroidal endothelial cells (MCECs) were incubated in media with soluble EDPs (kappa elastin, mouse elastin, and Val-Gly-Val-Ala-Pro-Gly [VGVAPG] hexapeptide) for different time intervals with or without a6(IV)NC1. The MCECs proliferation, migration, tube formation, MT1-MMP expression, and angiogenic signaling were analyzed in cells subjected to EDP and a6(IV)NC1 treatments. The MCECs also were subjected to EDPs, and specific inhibitors for evaluation of focal adhesion kinase (FAK) and protein kinase B (Akt) phosphorylation.RESULTS. Kappa elastin, mouse elastin, and VGVAPG enhanced the migration, without affecting the proliferation of MCECs. The a6(IV)NC1 inhibited survival and EDP-activated migration of MCECs. The EDP-activated MCEC tube formation on matrigel also was inhibited by a6(IV)NC1. Further, EDP-activated MT1-MMP expression and FAK/phosphoinositide-3-kinase (PI-3K)/mammalian target of rapamycin (mToR)/Akt phosphorylation in MCECs, were reduced by a6(IV)NC1. The EDP-induced FAK and Akt phosphorylation was blocked by FAK-and Akt-specific inhibitors.CONCLUSIONS. The EDPs and a6(IV)NC1 are identified to exhibit opposing effects on MCEC angiogenic behavior and signaling. The a6(IV)NC1 inhibited cell survival, EDP-mediated migration, MT1-MMP expression and, FAK/PI-3K/mToR/Akt phosphorylation in MCECs. This work demonstrates a6(IV)NC1 as a prospective endogenous molecule for the treatment of diseases involving choroidal neovascularization in the eye.Keywords: elastin-derived peptides, noncollagenous domains of type IV collagen, angiogenesis P athologic progression of choroidal neovascularization (CNV) in the wet form of age-related macular degeneration (AMD) includes the activation of angiogenic behavior in choroidal endothelial cells. This is promoted by different pathologic factors, including extracellular matrix (ECM) derivatives. 1,2 Elastins and type IV collagen constitute major components of ECM in different tissues, such as skin, lungs, vascular basement membrane (VBM) of blood vessels, and ocular tissues.3,4 Degradation of elastin was identified as a pathologic factor leading to the progression of CNV, through substantial histologic, genetic, and clinical studies, with significant focus on elastin degradation products (EDPs). 1,2Histologic studies revealed conspicuous fragmentation and decrease in the thickness of Bruch's membrane-elastin layer in patients with AMD. Thus, damage in elastic Bruch's membrane was identified to promote ...

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