Thirty Days of an Oral Simvastatin Intervention Does Not Change Nitric Oxide-Mediated Micro- and Macrovascular Endothelial Function in Women with Endometriosis

Purpose: Endometriosis is characterized by the presence of endometrium-like tissue outside the uterine cavity. This estrogen-dependent disease is associated with systemic inflammation and increased risk of cardiovascular disease. In primate models of endometriosis, systemic treatment with simvastatin reduces endometrial lesion load. Seven days of atorvastatin improves nitric oxide (NO)-mediated endothelial function in women with endometriosis, but the impact of a longer intervention with simvastatin that specifically targets endometriosis-associated inflammation has yet to be investigated. We hypothesized a thirty-day oral simvastatin intervention would improve NO-mediated micro- and macrovascular endothelial function in women with endometriosis. Methods: In seven women with laparoscopically confirmed endometriosis, cutaneous microvascular function and brachial artery flow-mediated dilation (FMD) were measured at baseline and following a thirty-day simvastatin intervention (10mg/day). In a subset of five women, FMD+Handgrip (HG) was also measured before and after the intervention. Two intradermal microdialysis fibers were placed into the ventral forearm skin. Laser-Doppler flowmetry was used to measure cutaneous blood flow while increasing concentrations of acetylcholine (10-10 to 10-1 M; endothelium-dependent vasodilator) were perfused with a control (lactated Ringer’s; CTL) or a non-specific NO synthase inhibitor (15 mM N G-nitro-L-arginine methyl ester; L-NAME) set to a thermoneutral 33 °C. Following the dose-response protocol, maximal cutaneous vasodilation was induced by increasing local skin temperature to 43 °C and perfusing 28 mM sodium nitroprusside. Cutaneous vascular conductance (CVC) was calculated as the quotient of red blood cell flux over mean arterial pressure and normalized as a percentage of the site-specific maximum (CVC%max). Area under the dose-response curve (AUC) of the CTL and L-NAME sites were calculated using the trapezoid rule. FMD and FMD+HG are expressed as the percent change in brachial artery diameter in response to post-occlusive reactive hyperemia (PORH) and PORH+HG at 20% maximum voluntary contraction relative to baseline, respectively. FMD baseline diameter was continuously measured for 2 min, cuff occlusion for 5 min, and post-occlusion for 4 min, where FMD+HG was a 3 min cuff occlusion with HG (GE Logiq E). Edge detection software (Cardiovascular Suite 4) was utilized. Results: In the cutaneous microcirculation, there was no main effect of simvastatin treatment (p =0.46) or localized NO synthase inhibition (p =0.55) following a thirty-day simvastatin treatment [Mean (SD): Baseline - CTL: 273 (121) vs. L-NAME: 191 (109); Simvastatin - CTL: 251 (102) vs. L-NAME: 279 (131) AU]. Simvastatin treatment also did not alter %FMD [Baseline: 4.73 (2.96)% vs. Simvastatin: 5.50 (2.99)%; p =0.61] and %FMD+HG [Baseline: 8.65 (3.75)% vs. Simvastatin: 9.48 (4.56)%; p =0.66] in women with endometriosis. Conclusion: Thirty-days of an oral simvastatin intervention did not alter NO-mediated micro- and macrovascular endothelial function in women with endometriosis. The data suggest that the duration, dose, and class of statin is important for targeting peripheral vascular function in women with endometriosis. Diversity Supplement R01 HL161000-02S2 (VGC), NIH F31 HL170616-0 (ACW), NIH Grant R01 HL161000 (NSS, LMA) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process. Information & Authors Information Published In Physiology Volume 40 • Issue S1 • May 2025 Copyright Copyright © 2025 Int. Union Physiol. Sci./Am. Physiol. Soc. History Published in print: May 2025 Published online: 12 May 2025

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