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

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Circulation Research (Impact Factor: 11.02). 12/2007; 101(11):1185-93. DOI: 10.1161/CIRCRESAHA.107.157586
Source: PubMed


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.

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    • "Likewise, the young rats benefited from the early upregulation of genes required for endothelial cell proliferation and migration, including Cib1 and Lef1 mRNAs. CIB1 is a calcium and integrin-binding protein-1 that is essential for proper EC signaling and function such as migration, proliferation, and nascent tubule formation, and therefore is critical in ischemia-induced angiogenesis in the retina, as well as ischemia-induced adaptive angiogenesis (Zayed et al., 2007). "
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    Frontiers in Aging Neuroscience 03/2014; 6:44. DOI:10.3389/fnagi.2014.00044 · 4.00 Impact Factor
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    • "It was further shown that CIB1-induced PAK1 activation is inhibitory to cell migration due to an LIM kinase-dependent increase in cofilin phosphorylation [Leisner et al., 2005]. However, the same group later showed that genetic ablation of CIB1 reduced endothelial cell migration on Fn and adhesion dependent PAK1 and Erk1/2 activation [Zayed et al., 2007]. Since PAK1 is also known to promote cell migration, it appears that PAK1 is able to regulate cell migration both positively and negatively [Ching et al., 2007; Huynh et al., 2010]. "
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    Journal of Cellular Biochemistry 11/2011; 112(11):3289-99. DOI:10.1002/jcb.23255 · 3.26 Impact Factor
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    • "These results suggest that pharmacological blocking of CIB1 could be a means to specifically suppress pathological cardiac hypertrophy. However, since CIB1 is expressed in a wide variety of tissues, CIB1 inhibitors likely would have to be cardiac-specific to circumvent side effects in other tissues such as impaired angiogenesis following ischemia, impaired thrombosis or male sterility, all of which were observed in Cib1 knockout mice (Naik et al., 2009; Yuan et al., 2006; Zayed et al., 2007). "
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