Class IA Phosphatidylinositol 3-Kinase Isoform p110α Mediates Vascular Remodeling

Abstract

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 (p110α, p110β, p110δ), 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 p110α (PIK-75), p110β (TGX-221), and p110δ (IC-87114), respectively. We identified p110α to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110β and p110δ activities were dispensable. Surprisingly, p110δ 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 p110α deficiency (sm-p110α −/− ). Targeted deletion of p110α in sm-p110α −/− mice blunted growth factor–induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110δ deficiency did not affect vascular remodeling in vivo. Conclusions— Receptor tyrosine kinases–induced phosphatidylinositol 3′-kinase signaling via the p110α isoform plays a central role for vascular remodeling in vivo. Thus, p110α represents a selective target for the prevention of neointima formation after vascular injury, whereas p110β and p110δ expression and activity do not play a significant role.

PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

“…By using a gene silencing strategy, they confirmed an essential role for p110a in SMC proliferation following PDGF stimulation but surprisingly also identified that p110d silencing affected SMC proliferation, suggesting a non-catalytic role of this isoform downstream of PDGFR activation (Vantler et al, 2015). To further investigate a possible role for p110a in the restenosis process, the authors developed a mouse model where p110a had been specifically invalidated in SMC using the Cre/LoxP system with Cre expressed under the promoter of SM22a.…”

“…Different studies have recently investigated the possibility of blocking the activity of several class IA isoforms to prevent SMC proliferation in vitro and in vivo. In rat and human aortic SMC, Vantler et al found that the three class IA isoforms, a, b and d, were expressed whereas p110d was previously reported to be restricted to hematopoietic cells (Vantler et al, 2015).…”

“…One study clearly identified that a class III (Cain et al, 2010) Cellecell junction (Cain et al, 2010) VEGF-induced migration (Graupera & Potente, 2013), proliferation (Vantler et al, 2015) and e-NOS phosphorylation (Igarashi & Michel, 2001), Transendothelial migration under an MCP-1 gradient (Cain et al, 2010) Platelets…”

“…This p110a deficiency in mice also largely suppressed balloon injury-induced neointima formation, confirming in vitro data, whereas p110d deletion did not. These interesting data (Vantler et al, 2015) raise some important questions. The first concerns the true role of p110d in arterial cells.…”

“…These results suggest a possible function for PI3Ka in the endothelial reparative mechanism following arterial injury in interventional cardiology. To this end, Vantler et al showed that targeting PI3Ka activity with a specific PI3Ka inhibitor leads to a defect in endothelial cell proliferation induced by VEGF, indicating that the therapeutic application of p110a inhibitors in the context of interventional cardiology may also affect the reendothelialization process (Vantler et al, 2015). However, these results are in contrast to another recent study where pharmacological administration of the specific PI3Ka inhibitor PIK75 selectively interfered with arterial thrombosis and neointima formation without perturbing neither reendothelialization in vivo nor endothelial cell proliferation in vitro (Holy et al, 2014).…”