Marfan syndrome (MFS) is an autosomal dominant disorder secondary to mutations that alter the expression or function of the extracellular protein fibrillin-1. The major cause of morbidity and mortality for afflicted patients is cardiovascular disease, including thoracic aortic aneurysms and dissection. Current treatments for MFS include anti-hypertensive medications such as losartan, an angiotensin receptor blocker, and prophylactic surgery. The goal of this study was to evaluate the effects of oral losartan treatment on vascular reactivity throughout the length of the aorta in a mouse model of progressive MFS with an average life expectancy of 3 months due to aortic rupture (Fbn1ᵐgR/mgR, hereafter mgR) and age-matched controls (CT). The ascending, proximal thoracic, distal thoracic, and infrarenal aorta were isolated in physiological salt solution (PSS), placed on 40 µm wire, and mounted onto the jaws of a DMT wire myograph. Following normalization of each segment to a wall tension equivalent of 100 mmHg, aortic vasoreactivity was then assessed via concentration response curves (CRCs) to phenylephrine (PE), acetylcholine (ACh), and Diethylamine-NONOate (DEA). Following CRCs, aortic vasoreactivity was further examined to increasing concentrations of isosmotic KCl (20, 40, 80 mM). We observed reduced α1-adrenergic mediated vasoconstriction to PE in mgR mice in the proximal and distal thoracic aortas, but not the ascending or infrarenal aortas. Losartan treatment had little impact on vasoconstriction to PE in mgR mice, however, losartan reduced the Fmax to PE in CT mice in the ascending, proximal thoracic, and distal thoracic aortas. Endothelial dependent vasodilation to the muscarinic receptor agonist, ACh, was attenuated in mgR mice compared to CT mice in the proximal and distal thoracic aortas, but not the ascending or infrarenal aortas. Losartan treatment increased maximal vasodilation to ACh in all strains and aortic segments, with exception of the infrarenal aorta. Vascular smooth muscle-dependent vasodilation to the nitric oxide donor, DEA, was reduced in mgR mice in the proximal thoracic, distal thoracic, and infrarenal aortas, but not the ascending aorta. Losartan significantly improved vasodilation to DEA in the proximal thoracic aorta in mgR mice, with minimal effects on the other aortic segments. KCl-mediated vasoconstriction was greatly reduced in mgR mice for all concentrations and all aortic segments, with the exception of the infrarenal aorta. Surprisingly, Losartan treatment had no impact on KCl-mediated vasoconstriction in mgR mice, but significantly reduced the Fmax in CT mice in all aortic segments, except the infrarenal aorta. Altogether, these data demonstrate the regional heterogeneity in vascular function of discrete aortic segments in mgR compared to CT mice following oral losartan treatment. Collectively, these data suggest that losartan improves aortic endothelial function in the thoracic aorta in the mgR mouse model. This study highlights the importance of understanding the effect of medical therapies on regional vascular function in MFS to improve care for afflicted patients. This abstract was presented at the American Physiology Summit 2026 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.
Sveeggen et al. (Fri,) studied this question.