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(Circulation Research. 2007;101:1185.)
© 2007 American Heart Association, Inc.

Integrative Physiology

CIB1 Regulates Endothelial Cells and Ischemia-Induced Pathological and Adaptive Angiogenesis

Mohamed A. Zayed, Weiping Yuan, Tina M. Leisner, Dan Chalothorn, Andrew W. McFadden, Michael D. Schaller, M. Elizabeth Hartnett, James E. Faber, Leslie V. Parise

From the Departments of Pharmacology (M.A.Z., A.W.M., L.V.P.), Biochemistry and Biophysics (W.Y., T.M.L., L.V.P.), Cell and Molecular Physiology (D.C., J.E.F.), Cell and Developmental Biology (M.D.S.), and Ophthalmology (M.E.H.), Carolina Cardiovascular Biology Center (J.E.F., L.V.P.), and Lineberger Comprehensive Cancer Center (L.V.P.), The University of North Carolina at Chapel Hill.

Correspondence to Leslie V. Parise, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, CB#7260, Chapel Hill, NC 27599-7260. E-mail parise{at}med.unc.edu

Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. CIB1 (calcium- and integrin-binding protein), a 22-kDa EF-hand–containing protein, modulates the activity of p21-activated kinase 1 in fibroblasts. Because p21-activated kinase 1 also contributes to endothelial cell function, we hypothesized that CIB1 may have a role in angiogenesis. We found that endothelial cells depleted of CIB1 by either short hairpin RNA or homologous recombination have reduced migration, proliferation, and tubule formation. Moreover, loss of CIB1 in these cells decreases p21-activated kinase 1 activation, downstream extracellular signal-regulated kinase 1/2 activation, and matrix metalloproteinase 2 expression, all of which are known to contribute to angiogenesis. Consistent with these findings, tissues derived from CIB1-deficient (CIB1^–/–) mice have reduced growth factor–induced microvessel sprouting in ex vivo organ cultures and in vivo Matrigel plugs. Furthermore, in response to ischemia, CIB1^–/– mice demonstrate decreased pathological retinal and adaptive hindlimb angiogenesis. Ischemic CIB1^–/– hindlimbs also demonstrate increased tissue damage and significantly reduced p21-activated kinase 1 activation. These data therefore reveal a critical role for CIB1 in ischemia-induced pathological and adaptive angiogenesis.

Key Words: angiogenesis • endothelial cells • ischemia • CIB1 • PAK1