Noncatalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage.

Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase gamma (PI3K gamma) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3K gamma in the vascular wall during intimal hyperplasia using PI3K gamma-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3K gamma in vascular smooth muscle cells (VSMCs) leads to modulation of cell proliferation, associated with an increase in intracellular CAMP levels. Real-time analysis of cAMP dynamics revealed that P13K gamma modulates the degradation of cAMP in primary VSMCs independently of its kinase activity through regulation of the enzyme phosphodiesterase 4. Importantly, the use of an N-terminal competing peptide of PI3K gamma blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3K gamma in arterial remodeling and reveal novel strategies targeting the docking function of PI3K gamma for the treatment of cardiovascular diseases.