The integrin coactivator kindlin-2 plays a critical role in angiogenesis in mice and zebrafish. Blood 2011 May 05;117(18):4978-87
Date
03/08/2011Pubmed ID
21378273Pubmed Central ID
PMC3100704DOI
10.1182/blood-2010-11-321182Scopus ID
2-s2.0-79955980408 (requires institutional sign-in at Scopus site) 66 CitationsAbstract
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.
Author List
Pluskota E, Dowling JJ, Gordon N, Golden JA, Szpak D, West XZ, Nestor C, Ma YQ, Bialkowska K, Byzova T, Plow EFAuthor
Yan-Qing Ma PhD Associate Investigator in the Blood Research Institute department at BloodCenter of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBase 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
