PUBLICATION
The integrin co-activator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish
- Authors
- 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.
- ID
- ZDB-PUB-110317-35
- 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
Citation
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. (2011) The integrin co-activator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish. Blood. 117(18):4978-4987.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping