Regulation of Tumor Angiogenesis and Choroidal Neovascularization by Endogenous Angioinhibitors

Abstract

Angiogenesis is the process of neovascularization from parent blood vessels, which is a prerequisite for many physiological and pathological conditions and is regulated by a balance between endogenous angioinhibitors and angioactivators or angiogenic factors. Imbalance between angioinhibitors and angioactivators is associated with neovascularization capacity during progression of tumor development and Choroidal Neovascularization (CNV). Normalization of pathological angiogenesis is considered as an alternative strategy to prevent the tumor growth in cancer progression or retinal damage in CNV. Various angioinhibitors are being identified and evaluated for their pathological angiogenesis regulation, of which endogenous angioinhibitors are one class derived either from extra cellular matrix or from non-extra cellular matrix of human origin. Endogenous angioinhibitors are gaining much significance as they interact with proliferating endothelial cells by binding to distinct integrins and non-integrin receptors, regulating different intracellular signaling mechanisms leading to inhibition of choroidal neovascularization and tumor growth. This review will focus on endogenous angioinhibitors and their receptor(s) mediated angioinhibitory signaling, which are of major concern in angiogenesis and their clinical and pharmaceutical implications.

Keywords: Angiogenesis; Endothelial Progenitor Cells (EPCs); Pigment epithelium derived factor (PEDF); Vasoinhibins.

Figure 1. Schematic illustration of ECM derived endogenous angioinhibitors’ signaling

Tumstatin, endostatin, arresten and canstatin interact with αVβ3/ α3β1, α5β1, α1β1 and αVβ3/ αVβ5 integrins respectively, to inhibit the phosphorylation of focal adhesion kinase (FAK). Tumstatin: It binds to αVβ3 and α3β1 integrins and inhibits phosphorylation of FAK, PI3-K, Akt, mTOR, eIF4E and 4E-BP1 to decrease endothelial cell protein synthesis and proliferation. In addition tumstatin also inhibits NF B mediated signaling in hypoxic conditions leading to the inhibition of COX-2, VEGF and bFGF expressions, resulting in inhibition of hypoxic tumor angiogenesis and LASER induced CNV. Endostatin: It binds to α5β1 integrin and inhibits phosphorylation of FAK, causes inhibition of Ras, Raf, extra cellular signal related kinase-1 (ERK1) and p38 MAPK pathways that leads to inhibition of endothelial cell migration and tube formation and promotes apoptosis in LASER induced CNV. Arresten: It binds to α1β1 integrin and inhibits phosphorylation of FAK, causes inhibition of Ras, Raf, ERK1 and p38 MAPK pathways that leads to inhibition of HIF-1a addition arresten initiates two apoptotic pathways, involving activation of caspase-9 and -8, leading to activation of caspase-3 and PARP cleavage. (a) Arresten activates caspase-3 directly through inhibition of FAK/p38-MAPK/ Bcl-2/Bcl-xL and activation of caspase-9; (b) Integrin a1b1 cross talk with Fas-L through mitochondrial pathway and leads to activation of caspase-8 and-3 in proliferating endothelial cells. Canstatin: It binds to αVβ3/ αVβ5 integrins and inhibits two apoptotic pathways, involving activation of caspase-8 and casoase-9, leading to activation of caspase-3. Canstatin activates procaspase-9 not only through inhibition of the FAK/PI3K/AKT pathways but also by integrins cross talking mitochondrial pathway through Fas-L dependent caspase-8 activation leads to endothelial cell apoptosis in LASER induced CNV models. CM represents cell membrane. Hexastatin: Its receptor and mediated signaling is not yet known.

Figure 2. Schematic illustration of non-collagenous ECM derived endogenous angioinhibitors’ signaling

Angiostatins: Bind ATP synthases, αVβ3 integrin and angiomotin. Inhibit FAK activity by binding of integrins and ATP synthase of ECs. Endorepellin: Binds α2β1 integrins and VEGFR-2. Binding to α2β1, TSP-1 activates cAMP-PKA/FAK/p38-MAPK/Hsp27. Thrombospondins (TSPs): Bind to CD36 and integrin associated protein (IAP) promoting Src-family protein kinases/Caspase-3/p38 MAPK leading to apoptosis; different integrins (α3β1), CD47 and heparan sulfated proteoglycans (HSPGs) and TGF- β promoting tumor cell death.

Figure 3. Schematic illustration of non-ECM derived endogenous angioinhibitor signaling

Vasoinhibins: Bind probably prolactin receptor (PLR) and IL-1β. Inhibits Sos/Ras/MAPK, NOs/Raf/MAPK, and Ca2+/eNOs/ protein phosphatase 2 signaling. Promotes Ras/Tiam-1/Rac-1/Pak1 and Bcl-Xs mediated apoptosis.