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Background: An increase in aortic stiffness is a fundamental component of hypertension. However, the molecular mechanism involved is unclear. Our hypothesis is that the increased aortic stiffness in hypertension is partially due to the activation of serum response factor (SRF) /myocardin in vascular smooth muscle cells (VSMCs). Methods: 4 months old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Aortic pressure and stiffness were measured by a Millar catheter and by Doppler imaging echocardiography, respectively. VSMCs were isolated from thoracic aorta (TA), then cultured and tested at passages 2 to 4. Real time PCR and western blot were used to detect the gene and protein expression. Results: Aortic pressure was higher in SHR than WKY (mean arterial pressure (MAP) 138.7±11.8 vs 102.7±7 mmHg, p p p p p In vitro , CCG-100602, a specific inhibitor of SRF/myocardin interaction, not only strikingly repressed the increase of the expression in SRF, myocardin and the downstream targets α-SMA and SM22, but also blocked the nuclear translocation of myocardin in TA VSMCs from SHR ( p In vivo , 2-week treatment with CCG-100602 significantly reduced MAP and ASI by 19% and 63% in SHR, respectively ( p Conclusion: The activation of myocardin/SRF in aortic VSMCs presents a novel mechanism of increased aortic stiffness in SHR.