ZFIN ID: ZDB-PUB-110317-35
The integrin co-activator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish
Pluskota, E., Dowling, J.J., Gordon, N., Golden, J.A., Szpak, D., West, X.Z., Nestor, C., Ma, Y.Q., Bialkowska, K., Byzova, T., and Plow, E.F.
Date: 2011
Source: Blood   117(18): 4978-4987 (Journal)
Registered Authors: Dowling, Jim
Keywords: none
MeSH Terms:
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cytoskeletal Proteins/antagonists & inhibitors
  • Cytoskeletal Proteins/genetics
  • Cytoskeletal Proteins/physiology*
  • Female
  • Gene Knockdown Techniques
  • Integrin alphaVbeta3/physiology
  • Male
  • Mice
  • Mice, Knockout
  • Neovascularization, Pathologic/pathology
  • Neovascularization, Pathologic/physiopathology*
  • Neovascularization, Physiologic/physiology*
  • Oligodeoxyribonucleotides, Antisense/genetics
  • Prostatic Neoplasms/blood supply
  • Prostatic Neoplasms/physiopathology
  • Signal Transduction
  • Vascular Endothelial Growth Factor A/physiology
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
PubMed: 21378273 Full text @ Blood
FIGURES
ABSTRACT
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 as compared to 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 bone marrow 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 pathological and developmental angiogenesis, which arises from defective activation of integrin αVβ3.
ADDITIONAL INFORMATION