Addition of endorepellin (right) causes activation of Hsp27 (green) and disassembly of actin stress fibers (red).

Blood vessel growth is suppressed by several proteins—such as endorepellin—that are anti-angiogenic only after they are generated as fragments of larger proteins. Now, Bix et al. (page 97) report two surprises of endorepellin action: it exerts its effects via an integrin that collagen I uses to promote angiogenesis; and it may operate via a heat shock protein to disassemble actin structures needed for motility.

Endorepellin is a COOH-terminal fragment of perlecan, a heparan sulfate proteoglycan that acts as a cofactor for pro-angiogenic factors such as FGF. The authors found that a segment of endorepellin was enough to prevent endothelial cell migration and formation of capillaries, and that it acted by disrupting the actin cytoskeleton and attachment sites. They found that the major functional receptor for endorepellin was α2β1 integrin, one of the collagen receptors. Treating cells with endorepellin resulted in clustering of α2β1 integrin, and these integrin clusters colocalized with collapsed actin bundles. As reorganization of actin filaments is crucial to cell migration and capillary morphogenesis, the authors reason that endorepellin halts these processes by taking apart actin filaments and focal adhesions.

Collagen I binding to integrin α2β1 decreases cAMP levels and the activity of protein kinase A, but endorepellin binding to the same integrin triggers the opposite results. Endorepellin binding also activates FAK, p38MAPK, and phosphorylation of Hsp27. FAK activation has been associated with disassembly of focal adhesions, and results with inhibitors suggest that the transient phosphorylation (or subsequent destruction) of Hsp27 may somehow prompt the disintegration of actin filaments.

Early steps in angiogenesis include proteolysis of matrix to make room for growing vessels. This proteolysis probably liberates protein fragments such as endorepellin, which damp down angiogenesis so that it does not become overactive. ▪