Abstract
Angiogenesis, the process of neovascularization fro m parent blood vessels, is a prerequisite for many physiologi- cal and pathological conditions that is regulated b y a balance between the levels of endogenous angiog enic stimu- lators and matrix reloaded angiogenic regulators. S everal non-collagenous carboxy terminal end domains in chains of type IV collagen matrix reloaded molecule s selectively interact with proliferating endotheli al cells by binding to distinct integrins and regulate intracel lular signaling and inhibit angiogenesis. This revi ew will focus on the current understanding of extra cellular matrix type IV collagen reloaded endogenous angiogenesis i nhibitors and their mechanism of action.
Highlights
An emerging area of research in cell biology is the discovery of extra cellular matrix (ECM) that is reloaded with proteolytic fragments from the basement membrane, which exert powerful anti-angiogenic or anti-tumarogenic activities
The first discovered ECM reloaded endogenous angiogenic inhibitory molecule is endostatin, a 20-kDa fragment of heparan sulfate proteoglycan derived from type XVIII collagen non-collagenous (NC1) domain is best characterized among endogenous angiogenic inhibitors
HIF-1α transcriptionally regulates VEGF expression in hypoxic cells and promotes angiogenesis in solid tumors (Carmeliet et al, 1998; Kung et al, 2000; Sudhakar et al, 2005). These findings suggest that HIF-1α is a prime target for anticancer therapies and this hypoxic inhibitory activity might be exploited for antiangiogenic therapy in the treatment of different solid tumor cancers, but more pre-clinical laboratory studies are needed
Summary
An emerging area of research in cell biology is the discovery of extra cellular matrix (ECM) that is reloaded with proteolytic fragments from the basement membrane, which exert powerful anti-angiogenic or anti-tumarogenic activities. Since initial discovery of endostatin as endogenous angiogenesis inhibitor, there has been an outburst in antiangiogenic research and in the number of endogenous molecules that are known to promote or inhibit angiogenesis (Iozzo and San Antonio, 2001; Marneros and Olsen, 2001; Ortega and Werb, 2002; Schenk and Quaranta, 2003; Sottile, 2004; Sudhakar, 2007) (Figure 1). Type IV collagen α1, α2, α3 and α6 chain carboxy terminal NC1 domains were demonstrated to be anti-angiogenic These molecules that are needed to assemble vascular basement membrane (VBM) to maintain the integrity of blood vessels and to prevent the leakage of fluids and loss of proteins can do the opposite actions under the different circumstances (called matrix reloaded); that is, they have both pro-angiogenic and anti-angiogenic activities (Iozzo and San Antonio, 2001; Nakamura and Matsumoto, 2005; Sudhakar and Boosani, 2008). Matrix reloaded endogenous type IV collagen derived angiogenic inhibitors mechanism of action are of high significance and is updated in this review
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