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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Available from: Tina Leisner
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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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    ABSTRACT: Despite the obvious clinical significance of post-stroke angiogenesis in aged subjects, a detailed transcriptomic analysis of post-stroke angiogenesis has not yet been undertaken in an aged experimental model. In this study, by combining stroke transcriptomics with immunohistochemistry in aged rats and post-stroke patients, we sought to identify an age-specific gene expression pattern that may characterize the angiogenic process after stroke. We found that both young and old infarcted rats initiated vigorous angiogenesis. However, the young rats had a higher vascular density by day 14 post-stroke. "New-for-stroke" genes that were linked to the increased vasculature density in young animals included Angpt2, Angptl2, Angptl4, Cib1, Ccr2, Col4a2, Cxcl1, Lef1, Hhex, Lamc1, Nid2, Pcam1, Plod2, Runx3, Scpep1, S100a4, Tgfbi, and Wnt4, which are required for sprouting angiogenesis, reconstruction of the basal lamina (BL), and the resolution phase. The vast majority of genes involved in sprouting angiogenesis (Angpt2, Angptl4, Cib1, Col8a1, Nrp1, Pcam1, Pttg1ip, Rac2, Runx1, Tnp4, Wnt4); reconstruction of a new BL (Col4a2, Lamc1, Plod2); or tube formation and maturation (Angpt1, Gpc3, Igfbp7, Sparc, Tie2, Tnfsf10), had however, a delayed upregulation in the aged rats. The angiogenic response in aged rats was further diminished by the persistent upregulation of "inflammatory" genes (Cxcl12, Mmp8, Mmp12, Mmp14, Mpeg1, Tnfrsf1a, Tnfrsf1b) and vigorous expression of genes required for the buildup of the fibrotic scar (Cthrc1, Il6ra, Il13ar1, Il18, Mmp2, Rassf4, Tgfb1, Tgfbr2, Timp1). Beyond this barrier, angiogenesis in the aged brains was similar to that in young brains. We also found that the aged human brain is capable of mounting a vigorous angiogenic response after stroke, which most likely reflects the remaining brain plasticity of the aged brain.
    Full-text · Article · Mar 2014 · Frontiers in Aging Neuroscience
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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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    ABSTRACT: Calcium- and integrin-binding protein 1 (CIB1) has been shown to be involved in cell spreading and migration. The signaling events regulated by CIB1 during cell migration are poorly understood. Here we found that accumulation of CIB1 at the tip of the filopodia requires an intact cytoskeleton. Depletion of CIB1 using shRNA affects formation of FAK- and phosphotyrosine-rich focal adhesions without affecting stress fiber formation. Overexpression of CIB1 results in cell migration on fibronectin and Erk1/2 MAP kinase activation. CIB1-induced cell migration is dependent upon Erk1/2 activation, since it is inhibited by the MEK-specific inhibitor PD98059. Furthermore, CIB1-induced cell migration, as well as Erk1/2 activation, is dependent on PKC, Src family kinases as well as PI-3 kinase as it is inhibited by bisindolylmaleimide 1, PP2, and wortmannin, respectively, in a dose-dependent manner. Co-expression of dominant-negative Cdc42 completely abolished CIB1-induced cell migration. Additionally, co-expression of constitutively active, but not dominant negative PAK1, a CIB1 binding protein, inhibited CIB1-induced cell migration. These results suggest that CIB1 positively regulates cell migration and is necessary for the recruitment of FAK to the focal adhesions. Furthermore, CIB1-induced cell migration is dependent on MAP kinase signaling and its function is attenuated by PAK1.
    Preview · Article · Nov 2011 · Journal of Cellular Biochemistry
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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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    ABSTRACT: Ca(2+)-calcineurin-NFAT signaling plays a major role in promoting pathological cardiac hypertrophy. Heineke et al. (2010) show that CIB1 strongly enhances calcineurin activation and cardiac hypertrophy upon pathological stress, likely by functioning as a scaffold protein that exposes calcineurin to the L-Type Ca(2+) channel and the sarcolemma.
    Preview · Article · Sep 2010 · Cell metabolism
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