The effect of estrogen on microvascular smooth muscle cells : implications for peripheral vascular disease

Abstract

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Although the risk factors of this disease are common to males and females, the prevalence of CVD is gender dependent. This suggests the implication of the female hormone, estrogen or 17βestradiol, in CVD. How estrogen affects various CVD has long been a dazzling question. Substantial amount of research has been undertaken to assess the effect of estrogen on various CVDs. To date the mechanisms by which estrogen affects CVD remain incompletely understood, particularly estrogen-evoked signaling in arteriolar inflammation, Raynaud’s phenomenon (RP), and hypertension. In this study, we mechanistically assessed the effect of estrogen on microvasculture, at which the aforementioned vascular pathologies are manifested. First, we showed that estrogen attenuated inflammation of human arteriolar smooth muscle cells. This anti-inflammatory effect of estrogen is achieved by inhibiting major events of phenotypic switch, namely proliferation and migration. This was mirrored by decreased activation of mitogenic extracellular signal–regulated kinase (ERK1-2) and focal adhesion kinase (FAK), involved in cell proliferation and migration, respectively. Further investigations showed that estrogen induced vascular smooth muscle cell (VSMC) senescence via the regulation of tumor suppressor genes, p53 and pRb. In addition, estrogen increased the expression of contractile differentiation markers: calponin and caldesmon. Therefore, due to the potential of estrogen to favorably modulate VSMC phenotype, our results may explain the lower incidence of CVDs in estrogen-replete premenopausal females. Then, we evaluated the effect a novel homoisoflavonoid, 7-O-methylpunctatin (MP), on arteriolar inflammation. We showed that MP decreased VSMC proliferation, migration, invasion, and adhesion. MP also attenuated adhesion of THP-1 monocytes to microVSMCs, abolished FBS-induced expression of MMP-2, MMP-9, and NF-κB, as well as red