Abstract 14160: Novel Role of Pyk2 in Vascular Wall Remodelling Following Balloon Injury
Introduction: Thrombin, a serine/threonine protease, besides its role in blood coagulation, plays a significant role as a mitogen and motogen to many cell types, including vascular smooth muscle cells (VSMCs). Thrombin mediates its effects via protease-activated receptors1-4 (PARs1-4) and G proteins, notably Gq/11 or G12/13 in the regulation of cell migration and proliferation. Activation of these G proteins via coupling to various PLCs leads to generation of second messenger molecules, DAG and IP3 which in turn results in increased intracellular calcium levels and protein kinase C activation. One of the signaling molecules whose activation process depends on calcium is Pyk2. But nothing is known in regard to the role of Pyk2, a non-receptor tyrosine kinase in thrombin-induced human aortic smooth muscle cell (HASMC) growth and migration and injury-induced vascular wall remodeling.
Objective: To investigate the role of Pyk2 in GPCR agonist thrombin-induced HASMC growth and migration and injury-induced vascular wall remodeling.
xMethods and results: Thrombin activated Pyk2 in a time-dependent manner and inhibition of its stimulation attenuated thrombin-induced HASMC migration and proliferation. Thrombin also activated Gab1, p115 RhoGEF, Rac1, RhoA and Pak1 in this sequence and interference with activation of these molecules attenuated thrombin-induced HASMC migration and proliferation. In addition, adenovirus-mediated expression of dominant negative Pyk2 inhibited thrombin-induced Gab1, p115RhoGEF, Rac1, RhoA and Pak1 stimulation. Balloon injury also caused activation of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA and Pak1 in the artery and these responses were sensitive to inhibition by dominant negative Pyk2. Furthermore, inhibition of Pyk2 activation resulted in reduced recruitment of SMC onto the luminal surface and their proliferation in the intimal region leading to suppression of neointima formation.
Conclusion: These results demonstrate for the first time that Pyk2 plays a crucial role in GPCR agonist thrombin-induced HASMC growth and migration as well as balloon injury-induced neointima formation.
- © 2012 by American Heart Association, Inc.