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Matrix-specific activation of Src and Rho initiates capillary morphogenesis of endothelial cells

Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

¹Correspondence: Department of Pathology, Research North, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215, USA. E-mail: dsenger{at}caregroup.harvard.edu

Interstitial collagen I stimulates microvascular endothelial cells to form solid cords that imitate precapillary structures found during angiogenesis. Time-lapse microscopy identified cell retraction and disruption of cell–cell contacts as early critical steps in collagen I-induced capillary morphogenesis. These early stages paralleled collagen I activation of Src kinase and GTPase Rho through ß1 integrins. The Src inhibitor PP2, dominant-negative Src, and Rho inhibitor exoenzyme C3 transferase each inhibited collagen I induction of actin stress fibers that mediate cell retraction and each inhibited capillary morphogenesis. Collagen I also disrupted VE-cadherin from intercellular junctions through a Src-dependent mechanism; both the Src inhibitor PP2 and dominant-negative Src preserved VE-cadherin localization to regions of cell–cell contact. An active Src mutant disrupted VE-cadherin and cell–cell contacts similarly to collagen I. In sharp contrast, laminin-1 did not induce capillary morphogenesis, and laminin-1 did not induce activation of Src or Rho. Rather, laminin-1 induced persistent activation of the GTPase Rac. Thus, these studies identify activation of Src and Rho as key mechanisms by which collagen I provokes capillary morphogenesis of microvascular endothelial cells, and they define marked differences between the functions of collagen I and laminin-1 in regulating endothelial cell morphogenesis.—Liu, Y., Senger, D. R. Matrix-specific activation of Src and Rho initiates capillary morphogenesis of endothelial cells.

Key Words: angiogenesis • collagen • laminin • ß1 integrins • VE-cadherin

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