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 (PI3K) 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 in the vascular wall during intimal hyperplasia using PI3K-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3K 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 PI3K 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 blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3K in arterial remodeling and reveal novel strategies targeting the docking function of PI3K for the treatment of cardiovascular diseases.

高血压和内膜增生中的动脉重塑涉及炎症和血流中断，两者均导致平滑肌细胞去分化和增殖。在这种情况下，我们先前的研究结果确定磷酸肌醇3激酶（PI3K）是动脉壁炎症过程中的重要因素。在这里，我们首次使用缺失PI3K的小鼠和表达该酶死于激酶的小鼠的内膜增生过程，首次确定了非造血性PI3K在血管壁中的激酶非依赖性作用。此外，我们发现血管平滑肌细胞（VSMC）中PI3K的缺乏导致细胞增殖的调节，与细胞内cAMP水平的升高有关。对cAMP动态的实时分析表明，PI3K通过调节磷酸二酯酶4来调节主要VSMC中cAMP的降解，而与其激酶活性无关。重要的是，使用PI3K的N末端竞争性肽可以阻断主要VSMC的增殖。这些数据提供了PI3K在动脉重塑中与激酶无关的作用的证据，并揭示了靶向PI3K对接功能的新型策略，可用于治疗心血管疾病。