Vascular and neural mechanisms of chronic lower leg heating in pregnant women with obesity

/ABSTRACT Obesity is a major risk factor for hypertensive disorders of pregnancy (HDP). The underlying mechanisms are largely unclear, but maternal vascular endothelial dysfunction is likely involved. Endothelial dysfunction in HDP could be attributed to 1) alterations in the L-arginine/nitric oxide (NO) pathway, and 2) an increase in endothelin- 1 (ET-1). Additionally, augmented sympathetic vasoconstriction may also contribute to HDP. Chronic (repeated) whole-body heat exposure has been shown to increase NO bioavailability, decrease ET-1, and cause functional and structural adaptations in the vasculature. All these can improve vascular function, attenuate sympathetic (re)activity, lower blood pressure (BP), and reduce cardiovascular risk in non-pregnant individuals. Whether this is also true after regional (lower leg) heating in high-risk pregnant women is unknown. Our central hypothesis is that chronic lower leg heating will be effective in improving vascular endothelial function and attenuating sympathetic vasoconstriction, leading to a reduction of the risk for HDP in pregnant women with obesity. The overarching goal of this proposal is to determine the vascular and neural effects of chronic lower leg heating in obese pregnancy. We plan to enroll 118 pregnant women with obesity between 12-14 weeks of gestation and randomly assign them to either an intervention group or a control group (1:1 ratio). Participants in the intervention group will perform 16 weeks of home-based lower leg heating via water immersion up to the knee in a circulated bath (water 42°C, 4 times/week, 45 min/session), whereas those in the control group will immerse their legs in a thermoneutral water bath (33°C) at the same frequency and duration. Participants will be evaluated at baseline and then at 28-30 weeks of gestation. Aim 1 will determine the effects of chronic lower leg heating on maternal vascular function and surrogate markers of HDP. We will measure brachial artery flow-mediated dilation and placental perfusion (ultrasound). Blood samples will be collected for the estimation of NO (via nitrate and nitrite analysis), L-arginine, asymmetric dimethylarginine, 3-nitrotyrosine, and ET-1. Angiogenic factors, in combination with ambulatory BP, will be used as surrogate markers of HDP. Aim 2 will determine the effects of chronic lower leg heating on sympathetic vasoconstriction and BP. We will measure sympathetic activity (microneurography), leg vascular conductance, and neurovascular transduction. Sympathetic reactivity will be assessed during a graded upright tilt. We will also measure 24-h ambulatory BP. The relationship between sympathetic (re)activity and BP will be evaluated. Finally, we will determine the association between changes in sympathetic vasoconstriction and endothelial function after intervention. Findings from this project will provide insight on the extent and potential mechanisms of how chronic lower leg heating works for improving vascular endothelial function and sympathetic vasoconstriction in pregnant women with obesity. Results obtained will set a foundation for future large multicenter clinical trials to determine the efficacy and generalizability of home-based lower leg heat therapy as a safe, ease-of-use, cost-effective, and non-drug approach for reducing the risk of HDP. Project Number: 1R01HL172349-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: QI FU | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $670,890 | Activity Code: R01 | Study Section: Clinical Integrative Cardiovascular and Hematological Sciences Study Section[CCHS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17234901A1