Estrogen exerts vascular protective effects, but the underlying mechanisms remain to be understood fully. In recent years, hydrogen sulfide (H(2)S) has increasingly been recognized as an important signaling molecule in the cardiovascular system. Vascular H(2)S is produced from L-cysteine, catalyzed by cystathionine γ-lyase (CSE). In our study, apolipoprotein E (ApoE)-deficient mice were ovariectomized and implanted with placebo (OVX mice) or 17β-estradiol (E(2)) pellets (OVX + E(2) mice). Compared with OVX mice, OVX + E(2) mice showed increased plasma H(2)S levels (P = 0.012) and decreased aortic lesion area (P = 0.028). These effects were largely reversed when supplementing with the irreversible CSE inhibitor DL-propargylglycine (PPG) in the OVX + E(2) + PPG mice. Meanwhile, the nitric oxide and prostacyclin-resistant responses to cumulative application of acetylcholine (ACh) were studied among all the three groups of femoral arteries. Compared with the arteries in the OVX group, the vasodilator sensitivity of arteries to ACh was increased in the OVX + E(2) group and attenuated in the OVX + E(2) + PPG group. E(2) and estrogen receptor (ER) α agonist 4',4″,4'″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol rapidly increased H(2)S release in human endothelial cells, but not partially selective ERβ agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile. These effects were inhibited by ER antagonist ICI 182780 or by protein kinase G (PKG) inhibitor KT5823. Furthermore, endothelial PKG activity was increased by E(2) (P = 0.003) and E(2)-induced vasodilation was inhibited by KT5823 (P = 0.009). In conclusion, the endothelial CSE/H(2)S pathway is activated by E(2) through PKG, which leads to vasodilation. These actions may be relevant to estrogen's anti-atherogenic effect.

Vascular endothelial growth factor C (VEGF-C) is correlated positively with clinical cervical cancer metastasis and survival. Previously we showed that VEGF-C directly activated actin-binding protein moesin, leading to the formation of membrane protrusions. However, whether VEGF-C alters cervical cancer cell adhesion to the extra-cellular matrix is currently unknown. In this study, we investigated the effects of VEGF-C on the formation of focal adhesion complexes, which provide anchoring sites for cell attachment to the extracellular matrix. On cultured cervical carcinoma cell line SiHa cells, VEGF-C enhanced focal adhesion kinase (FAK) phosphorylation. As a result, VEGF-C led to increased formation of focal adhesion complexes and enhanced migration and invasion, which was reversed by siRNA abrogating FAK. VEGF-C resulted in increased interaction of its receptor Flt-4 with non-receptor tyrosine kinase c-Src, leading to c-Src phosphorylation. The specific inhibitor of c-Src kinase, PP2, or the transfection with specific c-Src siRNA largely impaired VEGF-C-enhanced FAK phosphorylation, suggesting that Flt-4/c-Src cascade plays a central role in these processes. These results implied that VEGF-C promotes cervical cancer metastasis by activation of FAK protein through Flt-4/c-Src pathway.

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