Identification and characterization of new mechanisms in cardiovascular estrogen signaling

• Women before menopause are protected from cardiovascular disease compared to age-matched men through mechanisms associated with the female sex hormone estrogen. There are three known estrogen receptors named ERα, ERβ and GPR30/GPER1, which are all three receptors are expressed in the cardiovascular system. Most known cardiovascular effects of estrogen are reported to be mediated via ERα but much less information is available regarding the importance of ERβ and GPR30. The aim of this thesis was to further investigate the vascular importance of GPR30 and ERβ. Treatment of bEnd.3 endothelial cells with the inflammation promoter lipopolysaccharide (LPS) reduced expression of ERα and ERβ mRNA and protein by 20-70%. Treatment with estrogen up-regulated ERβ mRNA, and attenuated the LPS-induced down-regulation of ERβ. The down-regulation of the anti-inflammatory ERα by LPS may represent a new pro-inflammatory mechanism in the blood vessels. The estrogen-induced up-regulation of ERβ suggests that ERβ is involved in estrogen evoked vascular anti-inflammation. Treatment of endothelial cell lines with the GPR30 specific agonist G-1 reduced cell proliferation by 50-90%. Flow cytometry showed that G-1 blocks the endothelial cells from entering the mitosis phase. Treatment with G-1 completely stopped outgrowth of cells from aortic explants. Besides reducing proliferation through GPR30, G-1 also disrupted the microtubule structure through a GPR30 independent mechanism. Confluent A7r5 vascular smooth muscle cells display spontaneous and synchronized oscillations in intracellular Ca2+ concentration, called Ca2+ spikes. Treatment with G-1 acutely abolished the Ca2+ spikes, suggesting that GPR30 affects Ca2+ homeostasis, offering a possible mechanism through which GPR30 regulates blood pressure.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Keyword

endothelial cells

vascular smooth muscle cells

estrogen

GPR30/GPER1

inflammation

calcium

neovascularization

microtubule

Publication and Content Type

dok (subject category)

vet (subject category)