Vascular Gqα signaling has been shown to contribute to cardiac hypertrophy. In addition, angiotensin II (Ang II) was shown to induce VSMC hypertrophy through Gqα signaling, however, the studies on the role of Gqα and PLCβ1 proteins in VSMC hypertrophy in animal model are lacking. The present study was therefore undertaken to examine the role of Gqα/PLCβ1 proteins and the signaling pathways in VSMC hypertrophy using spontaneously hypertensive rats (SHR). VSMC from 16 week-old SHR and not from 12 week-old SHR exhibited enhanced levels of Gqα/PLCβ1 proteins as compared to age-matched Wistar-Kyoto (WKY) rats as determined by Western blotting. However, protein synthesis as determined by ³[H]leucine incorporation was significantly enhanced in VSMC from both 12 and 16 week-old SHR as compared to VSMC from age-matched WKY rats. Furthermore, the knockdown of Gqα/PLCβ1 in VSMC from 16 week-old SHR by antisense and siRNA resulted in attenuation of protein synthesis. In addition, the enhanced expression of Gqα/PLCβ1 proteins, enhanced phosphorylation of ERK1/2 and enhanced protein synthesis in VSMC from SHR were attenuated by Ang II AT1 and endothelin-1 (ET-1) ET_A receptor antagonists, losartan and BQ123 respectively but not by ET_B receptor antagonist, BQ788. In addition, PD98059 decreased the enhanced expression of Gqα/PLCβ1 and protein synthesis in VSMC from SHR. These results suggest that the enhanced levels of endogenous Ang II and ET-1 through the activation of AT1 and ET_A receptors respectively and MAP kinase signaling, enhanced the expression of Gqα/PLCβ1 proteins in VSMC from 16 week-old SHR and result in VSMC hypertrophy.