Thoracic aorta remodeling precedes third-order mesenteric contractile dysfunction in adiposity-induced hypertension in a sex-dependent manner

Introduction: : Hypertension and increased adiposity are highly prevalent comorbidities, yet there is limited biomechanics literature specifically addressing adiposity-induced hypertension. Previous research has highlighted the crucial interplay between central and peripheral vasculature in the development of hypertension. Both systems respond to and drive this condition, affecting each other's remodeling in the process. This research has primarily focused on male aortic stiffening and increased myogenic tone in angiotensin-II animal models of hypertension.
Dahl-Salt Sensitive (Dahl-SS) rats fed a high-fat diet serve as an established model for studying adiposity-induced hypertension, demonstrating increased blood pressure in both females and males over 24 weeks. Notably, research has shown that the active mechanical behavior of both the aorta and third-order mesenteric arteries, one of the most important peripheral vascular beds for blood pressure regulation, varies between sexes. Despite these findings, further investigation is needed to understand the interplay between the aorta and peripheral arteries, specifically the mesenteric arteries, in the development of adiposity-driven hypertension.
This study aims to quantify the mechanical remodeling occurring in the thoracic aorta and third-order mesenteric arteries in response to adipose-driven hypertension development in female and male Dahl-SS rats. We test the hypothesis that the mechanics of both central and peripheral arteries are affected by diet in this model of hypertension in a time dependent manner. Additionally, we explore whether the effects of a high-fat diet are modulated by sex.

Materials and

Methods: : We quantified the mechanical behavior of the thoracic aorta and third-order mesenteric arteries in female and male Dahl SS rats fed either a control-fat diet (10% fat, CFD) or a high-fat diet (60% fat, HFD) for 8 and 24 weeks after weaning. Mean arterial pressure (MAP) was measured via tail-cuff plethysmography before sacrifice. The arterial pressure in the third-order mesenteric arteries was estimated as 0.64 × MAP.
For the thoracic aorta, passive uniaxial ring tests were performed in the circumferential direction using a custom-made mechanical stretcher. Each ring was preloaded and then subjected to deformation sequences of 5 loading-unloading cycles, with elongations increasing from 10% to 80% in 10% increments at a deformation rate of 0.1 mm/s. Mechanical analysis was performed on the loading portion of the final cycle at 80% elongation.
For the third-order mesenteric arteries, both active (using calcium-containing physiological salt solution (PSS) at 37°C) and passive (using calcium-free PSS with 1 mM EGTA at room temperature) behaviors were tested across a pressure range from 20 to 120 mmHg in 20 mmHg increments. Contraction to the 1 adrenergic receptor agonist phenylephrine (500 nM; PE) was elicited at each pressure to assess the vessel’s contractile ability.
Stress-stretch curves were calculated for both vessel types. For mesenteric arteries, myogenic tone and the stress contribution of vascular smooth muscle cells (VSMCs) were also quantified. Statistical significance between groups was determined using a two-way ANOVA (p = 0.05), followed by Sidak’s correction for multiple comparisons.

Results, Conclusions, and Discussions:: Significant sex- and diet-dependent mechanical differences were observed at 8 weeks in the thoracic aorta, but not in the third-order mesenteric arteries. Specifically, aortas from males on an HFD exhibited higher structural stiffness (i.e., reached higher stress for equal stretch) than those on a CFD. Additionally, aortas from females showed higher structural stiffness compared to males, regardless of diet. The mechanical behavior of mesenteric arteries, however, was unaffected by sex or diet. Interestingly, these mechanical differences were not accompanied by a significant increase in blood pressure, suggesting they may precede a rise in blood pressure, at least in females.
At 24 weeks, significant sex- and diet-dependent mechanical differences were observed in the third-order mesenteric arteries, but not in the aorta. Differences in aortic structural stiffness were no longer evident. However, mesenteric arteries from males showed significantly increased myogenic tone, while females exhibited significantly decreased myogenic tone at physiologically relevant pressures in HFD-fed animals. Additionally, VSMC stress was significantly lower in HFD-fed females compared to males. No differences were found in PE-induced contractions or in active and passive stress-stretch curves, suggesting that changes in myogenic tone and VSMC stress do not result from a loss of contractile ability.
These mechanical changes were accompanied by a significant increase in both MAP and estimated in vivo mesenteric blood pressure in HFD-fed females but not males, which is somewhat unexpected. This indicates that the increased blood pressure in females does not stem from the increased mesenteric resistance commonly documented in males, and that the increased myogenic tone in males does not lead to higher blood pressure.
In conclusion, sex and diet significantly influence vascular remodeling and blood pressure regulation in Dahl SS rats. Understanding these differences is crucial for developing targeted treatments for adiposity-driven hypertension.

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