Ovariectomy-Induced Arterial Stiffening Differs from Vascular Aging and is Reversed by GPER Activation

Kilanowski-Doroh, I.; McNally, A. B.; Wong, T. J.; Visniauskas, B.; Blessinger, S. A.; Imulinde Sugi, A.; Richard, C.; Diaz, Z.; Horton, A.; Natale, C. A.; Ogola, B. O.; Lindsey, S. H.

doi:10.1101/2023.08.10.552881

bioRxiv · 10.1101/2023.08.10.552881

Ovariectomy-Induced Arterial Stiffening Differs from Vascular Aging and is Reversed by GPER Activation

Kilanowski-Doroh, I.·McNally, A. B.·Wong, T. J.·Visniauskas, B.·Blessinger, S. A.·Imulinde Sugi, A.·Richard, C.·Diaz, Z.·Horton, A.·Natale, C. A.·Ogola, B. O.·Lindsey, S. H.

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Abstract

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 (GPER) could reverse stiffness. Female C57Bl/6J mice were ovariectomized (OVX) at 10 weeks of age or aged to 52 weeks, and some mice were treated with GPER agonists. OVX and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while OVX increased material stiffness without altering vascular geometry. RNA-Seq analysis revealed that OVX downregulated smooth muscle contractile genes. The enantiomerically pure GPER agonist, LNS8801, reversed stiffness in OVX mice to a greater degree than the racemic agonist G-1. In summary, OVX and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling while OVX induced material stiffness independent of geometry and a loss of the contractile phenotype. This study helps to further our understanding of the impact of menopause on vascular health and identifies LNS8801 as a potential therapy to counteract this detrimental process in women.

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Kilanowski-Doroh, I., McNally, A. B., Wong, T. J., Visniauskas, B., Blessinger, S. A., Imulinde Sugi, A., Richard, C., Diaz, Z., Horton, A., Natale, C. A., Ogola, B. O., Lindsey, S. H.. 2023-08-14. Ovariectomy-Induced Arterial Stiffening Differs from Vascular Aging and is Reversed by GPER Activation. https://doi.org/10.1101/2023.08.10.552881

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