Class IA Phosphatidylinositol 3-Kinase Isoform p110 alpha Mediates Vascular Remodeling
2015 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 35, no 6, 1434-1444 p.Article in journal (Refereed) Published
Objective-Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3'-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3'-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3'-kinase isoforms (p110 alpha, p110 beta, p110 delta), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo. Approach and Results-Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases-dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110 alpha (PIK-75), p110 beta (TGX-221), and p110 delta (IC-87114), respectively. We identified p110 alpha to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110 beta and p110 delta activities were dispensable. Surprisingly, p110 delta exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell-specific p110 alpha deficiency (sm-p110 alpha(-/-)). Targeted deletion of p110 alpha in sm-p110 alpha(-/-) mice blunted growth factor-induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110 delta deficiency did not affect vascular remodeling in vivo. Conclusions-Receptor tyrosine kinases-induced phosphatidylinositol 3'-kinase signaling via the p110 alpha isoform plays a central role for vascular remodeling in vivo. Thus, p110 alpha represents a selective target for the prevention of neointima formation after vascular injury, whereas p110 beta and p110 delta expression and activity do not play a significant role.
Place, publisher, year, edition, pages
2015. Vol. 35, no 6, 1434-1444 p.
neointima, p110 alpha, p110 delta, phosphatidylinositol 3 '-kinase (PI3K), tyrosine kinase, vascular remodeling, vascular smooth muscle cells
Hematology Cardiac and Cardiovascular Systems
IdentifiersURN: urn:nbn:se:uu:diva-256209DOI: 10.1161/ATVBAHA.114.304887ISI: 000354820600019PubMedID: 25908763OAI: oai:DiVA.org:uu-256209DiVA: diva2:840028