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Impact of GPER, Sex, and Age on Arterial Stiffness and Fibrotic Gene Expression
Author(s) -
Kilanowski-Doroh Isabella M.,
Ogola Benard O.,
Harris Nicholas R.,
Gentry Kaylee,
Satou Ryousuke,
Lindsey Sarah H.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04847
Subject(s) - ctgf , arterial stiffness , gper , medicine , endocrinology , blood pressure , pulse wave velocity , biology , receptor , andrology , estrogen receptor , growth factor , cancer , breast cancer
Arterial stiffness is associated with cardiovascular risk independent of blood pressure. Previously, we showed that pulse pressure, a measure of arterial stiffness, is higher in female mice with global deletion of G protein‐coupled estrogen receptor (GPER) despite similar blood pressure. Additionally, we found that the GPER agonist, G1, provides protection from arterial remodeling. Therefore, the current study assessed the impact of GPER, sex, and age on arterial stiffness and aortic expression of four profibrotic genes: decorin (DCN), endothelin 1 (EDN1), type III collagen α1 (COL3A1), and connective tissue growth factor (CTGF). We hypothesized that global GPER knockout (KO) would increase fibrotic gene expression in females more than males, would be exacerbated with age, and would correlate with increased arterial stiffness. Methods Pulse wave velocity (PWV) was obtained in the carotid artery of 20 week‐old and 52 week‐old male and female wildtype and GPER KO mice (n = 3/group) using a Vevo 1100 high resolution ultrasound. RNA was isolated from aortas using a Qiagen RNeasy Mini Kit, and gene expression was quantified using droplet digital polymerase chain reaction (ddPCR). Statistical analysis was performed using three‐way ANOVA and Pearson r Correlation. Results In females, GPER deletion increased expression of all four profibrotic genes in 20 week‐old mice, but this relationship was reversed in 52 week‐old mice. In males, GPER deletion was associated with lower expression of fibrotic genes in both age groups. PWV significantly correlated with increased expression of CTGF (r = 0.66, p = 0.019) and EDN1 (r = 0.61, p = 0.036). In addition, the expression of CTGF, COL3A1, EDN1, and DCN were positively correlated (p < 0.005). Interestingly, expression of both ERα and GPER were increased with aging in female mice (p < 0.05). Conclusion Increased PWV was accompanied by upregulation of four profibrotic genes in the aorta. Adult female GPER KO mice had increased stiffness and higher expression of fibrotic genes. However, GPER deletion was associated with lower PWV and fibrotic gene expression in middle‐aged mice. Therefore, the protective effect of GPER in the vasculature was reversed with aging, despite the fact that aging upregulated estrogen receptor expression. Future studies will determine the mechanism by which GPER influences the expression of fibrotic genes and arterial stiffness. Support or Funding Information NIH HL133619