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The integrin coactivator kindlin-2 plays a critical role in angiogenesis in mice and zebrafish.

Blood | May 5, 2011

Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice and causes severe developmental defects in zebrafish. Knockdown of kindlin-2 levels in endothelial cells resulted in defective adhesive and migratory responses, suggesting that angiogenesis might be aberrant even with partial reduction of kindlin-2. This hypothesis has now been tested in the kindlin-2(+/-) mice. RM1 prostate tumors grown in kindlin-2(+/-) mice had fewer blood vessels, which were thinner and shorter and supported less tumor growth compared with wild-type littermates. The vessels that did form in the kindlin-2(+/-) mice lacked smooth muscle cells and pericytes and had thinner basement membranes, indicative of immature vessels. VEGF-induced angiogenesis in matrigel implants was also abnormal in the kindlin-2(+/-) mice. Vessels in the kindlin-2(+/-) mice were leaky, and BM transplantation from kindlin-2(+/-) to WT mice did not correct this defect. Endothelial cells derived from kindlin-2(+/-) mice had integrin expression levels similar to WT mice but reduced αVβ3-dependent signaling, migration, adhesion, spreading, and tube formation. Developmental angiogenesis was markedly impaired by kindlin-2 morpholinos in zebrafish. Taken together, kindlin-2 plays an important role in pathologic and developmental angiogenesis, which arises from defective activation of integrin αVβ3.

Pubmed ID: 21378273 RIS Download

Mesh terms: Animals | Base Sequence | Cell Line, Tumor | Cytoskeletal Proteins | Female | Gene Knockdown Techniques | Integrin alphaVbeta3 | Male | Mice | Mice, Knockout | Neovascularization, Pathologic | Neovascularization, Physiologic | Oligodeoxyribonucleotides, Antisense | Prostatic Neoplasms | Signal Transduction | Vascular Endothelial Growth Factor A | Zebrafish | Zebrafish Proteins

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Associated grants

  • Agency: NHLBI NIH HHS, Id: P01 HL073311
  • Agency: NIAMS NIH HHS, Id: 1K08AR054835
  • Agency: NHLBI NIH HHS, Id: R01 HL096062
  • Agency: NIAMS NIH HHS, Id: K08 AR054835
  • Agency: NHLBI NIH HHS, Id: P01 HL 073311

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