Estrogen Contributions to Microvascular Dysfunction Evolving to Heart Failure With Preserved Ejection Fraction

Figures

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  Figure 1. The regulation of endothelial function. All presented pathways affect the cytosolic Ca2+ concentration in VSM cells by regulating endothelial function, which determines constriction/relaxation. Solid arrows indicate stimulation and lines with a flattened end indicate inhibition. Dashed lines indicate translocation of the molecule. Green squares are receptors. Ang II, angiotensin-II; AT, angiotensin-II receptor; cGMP, cyclic guanosine monophosphate; GPR30, G-protein coupled estrogen receptor 30; E2, 17β-estradiol; EDHF, endothelial-derived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; ER, estrogen receptor; ET, endothelin-1 receptor; ET-1, endothelin-1; MAPK/ERK, mitogen-associated protein kinase/extracellular signal-regulated kinases; NO, nitric oxide; PGI2, prostacyclin; PI3K, phosphoinositide 3-kinase; PKG, protein kinase G; ROS, reactive oxygen species; TXA2, thromboxane A2.

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  Figure 2. E2 positively influences angiogenic pathways resulting in an increased angiogenic capacity of pre-menopausal women potentially protecting them from HFpEF. All represented pathways positively affect angiogenesis in the heart. Estrogens influence pro-angiogenetic processes, rendering women less susceptible for impaired angiogenesis. This potentially protects pre-menopausal women from HFpEF. AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; E2, 17β-estradiol; eNOS, endothelial nitric oxide synthase; ER, estrogen receptor; ERE, estrogen responsive element; ET, endothelin-1 receptor; ET-1, endothelin-1; GPR30, G protein-coupled estrogen receptor 30; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PI3K, phosphoinositide 3-kinase; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

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  Figure 3. The influence of E2 on (perivascular) fibrosis formation. (Perivascular) fibrosis formation is attenuated in women through E2-induced inhibition of collagen production. However, E2 receptor dimerization promotes fibrosis formation in men. GPR30 localization in men results in perivascular fibrosis formation, while GPR30 localization at the plasma membrane inhibits fibrosis formation in women. Yellow circles indicated with a “P” represent phosphorylated serine residues. ER-α is phosphorylated at Ser-118, while ER-β is phosphorylated at Ser108. Ang II, angiotensin II; AR, androgen receptor; ARE, androgen responsive element; ATR, angiotensin II receptor; Co-R, co-receptor; E2, 17β-estradiol; ER, estrogen receptor; ERE, ααestrogen responsive element; GPR30, G protein coupled receptor 30; iNOS, inducible nitric oxide synthase; RAMP3, receptor activity modifying protein 3; TGF-β, transforming growth factor-β.