Cardiovascular diseases (CVD) remain the leading cause of death in men and women. Biological sex plays a major role in cardiovascular physiology and pathological cardiovascular remodeling. Traditionally, pathological remodeling of cardiovascular system refers to the molecular, cellular, and morphological changes that result from insults, such as myocardial infarction or hypertension. Regular exercise training is known to induce physiological cardiovascular remodeling and beneficial functional adaptation of the cardiovascular apparatus. However, impact of exercise-induced cardiovascular remodeling and functional adaptation varies between males and females. This review aims to compare and contrast sex-specific manifestations of exercise-induced cardiovascular remodeling and functional adaptation. Specifically, we review (1) sex disparities in cardiovascular function, (2) influence of biological sex on exercise-induced cardiovascular remodeling and functional adaptation, and (3) sex-specific impacts of various types, intensities, and durations of exercise training on cardiovascular apparatus. The review highlights both animal and human studies in order to give an all-encompassing view of the exercise-induced sex differences in cardiovascular system and addresses the gaps in knowledge in the field.

We recently reported sex differences in mesenteric arterial function of the UC Davis type-2 diabetes mellitus (UCD-T2DM) rats as early as the prediabetic state. We reported that mesenteric arteries (MA) from prediabetic male rats exhibited a greater impairment compared to that in prediabetic females. However, when females became diabetic, they exhibited a greater vascular dysfunction than males. Thus, the aim of this study was to investigate whether the female sex hormone, estrogen preserves mesenteric arterial vasorelaxation in UCD-T2DM female rats at an early prediabetic state. Age-matched female Sprague Dawley and prediabetic (PD) UCD-T2DM rats were ovariectomized (OVX) and subcutaneously implanted with either placebo or 17β-estradiol (E2, 1.5 mg) pellets for 45 days. We assessed the contribution of endothelium-derived relaxing factors (EDRF) to acetylcholine (ACh)-induced vasorelaxation, using pharmacological inhibitors. Responses to sodium nitroprusside (SNP) and phenylephrine (PE) were also measured. Additionally, metabolic parameters and expression of some targets associated with vascular and insulin signaling were determined. We demonstrated that the responses to ACh and SNP were severely impaired in the prediabetic state (PD OVX) rats, while E2 treatment restored vasorelaxation in the PD OVX + E2. Moreover, the responses to PE was significantly enhanced in MA of PD OVX groups, regardless of placebo or E2 treatment. Overall, our data suggest that 1) the impairment of ACh responses in PD OVX rats may, in part, result from the elevated contractile responses to PE, loss of contribution of endothelium-dependent hyperpolarization (EDH) to vasorelaxation, and a decreased sensitivity of MA to nitric oxide (NO), and 2) the basis for the protective effects of E2 may be partly attributed to the elevation of the NO contribution to vasorelaxation and its interaction with MA as well as potential improvement of insulin signaling. Here, we provide the first evidence of the role of E2 in protecting MA from early vascular dysfunction in prediabetic female rats.

The beneficial cardiovascular effects of exercise are well documented, however the mechanisms by which exercise improves vascular function in diabetes are not fully understood. This study investigates whether there are (1) improvements in blood pressure and endothelium-dependent vasorelaxation (EDV) and (2) alterations in the relative contribution of endothelium-derived relaxing factors (EDRF) in modulating mesenteric arterial reactivity in male UC Davis type-2 diabetes mellitus (UCD-T2DM) rats, following an 8-week moderate-intensity exercise (MIE) intervention. EDV to acetylcholine (ACh) was measured before and after exposure to pharmacological inhibitors. Contractile responses to phenylephrine and myogenic tone were determined. The arterial expressions of endothelial nitric oxide (NO) synthase (eNOS), cyclooxygenase (COX), and calcium-activated potassium channel (KCa) channels were also measured. T2DM significantly impaired EDV, increased contractile responses and myogenic tone. The impairment of EDV was accompanied by elevated NO and COX importance, whereas the contribution of prostanoid- and NO-independent (endothelium-derived hyperpolarization, EDH) relaxation was not apparent compared to controls. MIE 1) enhanced EDV, while it reduced contractile responses, myogenic tone and systolic blood pressure (SBP), and 2) caused a shift away from a reliance on COX toward a greater reliance on EDH in diabetic arteries. We provide the first evidence of the beneficial effects of MIE via the altered importance of EDRF in mesenteric arterial relaxation in male UCD-T2DM rats.

Over the past decade obesity and type 2 diabetes (T2D) have reached epidemic levels worldwide. Cardiovascular disease (CVD) is one of the leading causes of mortality and morbidity in diabetic patients. Regular aerobic exercise is a well‐characterized lifestyle intervention that improves endothelial dysfunction, insulin resistance, and CVD risk in T2D. However, there are still debates regarding the duration and intensity of exercise required to ameliorate the deleterious metabolic perturbations in patients with T2D. The objective of this study was to investigate the effects of moderate intensity exercise (MIE) on vascular reactivity of mesenteric artery (MA) of male UC Davis Type‐2 Diabetes Mellitus Rat (UCD‐T2DM) model. Specifically, we examined whether there were changes in the relative contributions of endothelium‐derived relaxing factors in modulating vascular reactivity of MA from exercise‐trained compared with control sedentary UCD‐T2DM rats. Age‐matched male control and UCD‐T2DM rats underwent forced treadmill exercise (E) or remained sedentary (S) for 8 weeks. Endothelium‐dependent vasorelaxation (EDV) to acetylcholine (ACh, 10‐8 to 10‐5 M) were measured in precontracted MA before and after indomethacin (10µM), a cyclooxygenase (COX) inhibitor; followed by addition of L‐NAME (200µM), a nitric oxide synthase (NOS) inhibitor; followed by combination of apamin (1 µM) and TRAM‐34 (1 µM) (SKCa and IKCa blockers, respectively). The diabetic exercise trained (DE) rats exhibited decreased visceral adiposity and plasma triglyceride levels compared with the diabetic sedentary (DS) group. However, MIE did not alter plasma glucose or insulin concentrations in either nondiabetic or diabetic UCD‐T2DM Rats. Both sensitivity and maximal responses (Emax) to ACh were significantly reduced in MA from DS rats compared with those in control sedentary (CS). MIE improved the Emax to ACh only in MA of DE group. Inhibition of COX enhanced Emax to ACh in DS arteries suggesting the elevation of contractile COX metabolites in the DS group. The addition of L‐NAME resulted in a reduction in ACh relaxation of arteries from both CS and DS rats, however the effect was more prominent in DS group, suggesting the contribution of NO was enhanced (or endothelium‐dependent hyperpolarizing factor (EDHF)‐type relaxation was diminished) in DS arteries. Remarkably, MIE reversed the loss of EDHF‐type relaxation in UCD‐T2DM Rats. Unlike in the DS group, inhibition of COX had no effect on ACh response in MA of the DE group, suggesting that MIE may cause a shift from contractile COX to NO and EDHF‐type relaxation in UCD‐T2DM Rats. In conclusion, we provide the first evidence for a positive impact of moderate exercise on mesenteric arterial function in male UCD‐T2DM Rats, likely mediated by a contribution of EDHF‐type (NO and prostanoid‐independent) responses.

Evidence suggests that risk factors for cardiovascular diseases (CVD) are increased in the transgender population after they undergo cross-sex hormone therapy (CSHT). Although CSHT is essential, it may increase cardiometabolic risk in both male to female (MtF) and female to male (FtM) transgender cohorts. Several reports have shown that estrogen exerts direct beneficial effects on the vessel wall in healthy females. However, the vascular effects of testosterone are conflicting. The effects of CSHT in cardiovascular physiology of males or females are even less understood. The current study was, therefore, undertaken to evaluate the effects of estrogen and testosterone treatment on aortic reactivity in castrated (CAS) male and ovariectomized (OVX) female rats, respectively. Eight to ten weeks-old CAS male and OVX female rats were implanted subcutaneously with 1.5 mg 17β-estradiol (E2) (for CAS males) or 7.5 mg testosterone propionate (T) (for OVX females) or placebo (PL) containing pellet for about 35 days. Aged matched intact male (IM) and intact female (IF) rats were also included in the study. CAS+PL, CAS+E2 and IM were assigned in MtF group while OVX+PL, OVX+T and IF were assigned to FtM group. Endothelium-dependent vasorelaxation (EDV) to acetylcholine (ACh, 10-8 to 10-5 M) in aorta pre-contracted with phenylephrine (PE, 2 μM) was measured before and after pretreatment with indomethacin (10 μM, cyclooxygenase inhibitor), followed by L-NAME [200 μM, a nonselective nitric oxide (NO) synthase (NOS) inhibitor]. Sodium nitroprusside (SNP)-induced relaxation responses in endothelium-denuded rings in addition to the contractile responses to PE before and after L-NAME in aortic rings were also measured. EDV to ACh was significantly impaired in CAS+E2 group compared to CAS+PL and IM rats. This impairment was accompanied by a significant decrease in NO contribution to ACh-induced relaxation. Smooth muscle sensitivity to NO, as measured by SNP relaxations, was not altered, whereas the maximum contractile responses to PE was enhanced in the aortas of CAS+E2 group compared to IM. Endothelium-derived NO release during smooth muscle contraction, as assessed by the potentiation of the response to PE after NOS inhibition, was not altered in the aortas of MtF groups. Intriguingly, neither EDV to ACh nor PE contractile responses were altered in OVX+T compared to those in OVX+PL or IF in FtM group. Here, we provide the first evidence of impairment in aortic relaxation in CAS+E2 rats, in part via a decrease in the relative contribution of NO to the regulation of vascular relaxation responses or an increase in the contractile responses in this group. Additional studies will be needed to document the direction and underlying mechanisms of CSHT interaction with vasculatures. NIDA/NIGMS, 1SC1DA052120-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.