Citrulline Supplementation Improves Aortic Vasodilation and Prevents Aortic Thickening Only in Female Rats
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Updated: Oct 31, 2026
Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion
Published on: May 16, 2025
Katia Martinez-Gonzalez1, Patricia Campos-Bedolla2, Claudia Patlán-Lozano2
1Unidad Lerma, Universidad Autónoma Metropolitana, Mexico City, México.
Background:
Aging is associated with endothelial dysfunction and vascular remodeling, partly due to reduced nitric oxide (NO) bioavailability. l-citrulline, a precursor of l-arginine and NO synthesis, has been proposed as a therapeutic strategy to improve vascular function. This study evaluated the effects of chronic citrulline supplementation on aortic structure and vasodilatory function in adult male and female rats.
Methods:
Eight-month-old male and female Sprague-Dawley rats were randomly assigned to control or treatment groups. The treated animals received oral malate citrulline (1 g/kg/d) for 12 weeks. We isolated thoracic aortas for histological and morphometric analyses, including tunica media thickness and intima/media ratio. We assessed vascular reactivity in vitro using isolated aortic rings in an organ bath system, measuring acetylcholine (ACh)-induced relaxation following phenylephrine-induced contraction.
Results:
Citrulline supplementation significantly improved ACh-induced vasorelaxation in female rats compared with female controls (55.14% ± 4.8% vs 42.4% ± 4.3%, P < .05. No differences in vasorelaxation were observed in males between the treated and control groups. Histological analyses showed that treated females had less disruption of elastic fibers and a thinner minimal intima than controls, whereas males showed no structural differences.
Conclusions:
Citrulline supplementation improves endothelium-dependent vasodilation and may preserve aortic structural integrity in female rats but not in males. These findings suggest a sex-dependent vascular response to citrulline, potentially mediated by differences in NO signaling and hormonal regulation. Citrulline may represent a therapeutic strategy to improve vascular function during aging, particularly in females.
Clinical Impact:
The findings may guide clinical trials investigating how hormonal status and nitric oxide signaling affect the efficacy of citrulline supplementation in female patients. Ultimately, these insights could establish citrulline as a targeted, preventive intervention to preserve aortic structural integrity and reduce cardiovascular disease risk in the aging female population.
