Ovariectomy-Induced Arterial Stiffening Differs From Vascular Aging and Is Reversed by GPER Activation

Author:

Kilanowski-Doroh Isabella M.1ORCID,McNally Alexandra B.1ORCID,Wong Tristen1,Visniauskas Bruna1ORCID,Blessinger Sophia A.1ORCID,Imulinde Sugi Ariane1ORCID,Richard Chase12ORCID,Diaz Zaidmara1,Horton Alec1,Natale Christopher A.3ORCID,Ogola Benard O.4,Lindsey Sarah H.12ORCID

Affiliation:

1. Department of Pharmacology, Tulane School of Medicine, New Orleans, LA (I.M.K.-D., A.B.M., T.W., B.V., S.A.B., A.I.S., C.R., Z.D., A.H., S.H.L.).

2. Tulane Brain Institute, Tulane University, New Orleans, LA (C.R., S.H.L.).

3. Linnaeus Therapeutics, Haddonfield, NJ (C.A.N.).

4. Vascular Biology Center and Department of Medicine, Medical College of Georgia at Augusta University (B.O.O.).

Abstract

BACKGROUND: Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein–coupled estrogen receptor could reverse stiffness. METHODS: Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein–coupled estrogen receptor agonists. RESULTS: Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein–coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype. CONCLUSIONS: This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04130516.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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