Visniauskas, B. | bioRxiv Science

bioRxiv2023

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

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.

pharmacology and toxicology↗

bioRxiv2021

Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell Specific Changes in the Kidney that Lead to Elevated Blood Pressure and Salt Sensitivity

MicroRNA miR-181a is down-regulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a knockout mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radio-telemetry probes were implanted in twelve-week-old C57BL/6J wild-type and miR-181a/b-1 knockout mice. Systolic and diastolic BP were 4-5mmHg higher in knockout compared with wild-type mice over 24-hours (P<0.01). Compared with wild-type mice, renal renin was higher in the juxtaglomerular cells of knockout mice. BP was similar in wild-type mice on a high (3.1%) versus low (0.3%) sodium diet (+0.4{+/-}0.8mmHg) but knockout mice showed salt sensitivity (+3.3{+/-}0.8mmHg, P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA-sequencing in 6,699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, Smad4. We observed up-regulation of pathways related to the immune system, inflammatory response, reactive oxygen species and nerve development, consistent with higher tyrosine hydroxylase. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.

genomics↗