Coronary microvascular function and blood flow responses during acute exercise are impaired in the aged heart but can be restored by exercise training. Coronary microvascular resistance is directly dependent on vascular smooth muscle function in coronary resistance arterioles; therefore, we hypothesized that age impairs contractile function and alters the phenotype of vascular smooth muscle in coronary arterioles. We further hypothesized that exercise training restores contractile function and reverses age-induced phenotypic alterations of arteriolar smooth muscle. Young and old Fischer 344 rats underwent 10 wk of treadmill exercise training or remained sedentary. At the end of training or cage confinement, contractile responses, vascular smooth muscle proliferation, and expression of contractile proteins were assessed in isolated coronary arterioles. Both receptor- and non-receptor-mediated contractile function were impaired in coronary arterioles from aged rats. Vascular smooth muscle shifted from a differentiated, contractile phenotype to a secretory phenotype with associated proliferation of smooth muscle in the arteriolar wall. Expression of smooth muscle myosin heavy chain 1 (SM1) was decreased in arterioles from aged rats, whereas expression of phospho-histone H3 and of the synthetic protein ribosomal protein S6 (rpS6) were increased. Exercise training improved contractile responses, reduced smooth muscle proliferation and expression of rpS6, and increased expression of SM1 in arterioles from old rats. Thus age-induced contractile dysfunction of coronary arterioles and emergence of a secretory smooth muscle phenotype may contribute to impaired coronary blood flow responses, but arteriolar contractile responsiveness and a younger smooth muscle phenotype can be restored with late-life exercise training. NEW & NOTEWORTHY Aging impairs contractile function of coronary arterioles and induces a shift of the vascular smooth muscle toward a proliferative, noncontractile phenotype. Late-life exercise training reverses contractile dysfunction of coronary arterioles and restores a young phenotype to the vascular smooth muscle.
We have previously reported that in old rats, reversal of age‐related vascular dysfunction by exercise training correlates with an increase in circulating adiponectin and its signaling within coronary vascular smooth muscle. In the current study, we investigated the effect of deletion of adiponectin on exercise training‐induced vascular adiponectin. C57BL/6 wild‐type (WT) or homozygous adiponectin knockout (AdipoKO) mice were obtained at 10–12 wks of age and underwent treadmill exercise training (EX) (12 m/min, 5° incline, 1 hr/day, 5 days/wk for 8 wks) or remained sedentary (SED) in cages. Arterioles isolated from cardiac and soleus muscle were assessed for contractile and vasodilatory function, and capillarity of the soleus muscle was evaluated. Exercise training increased flow‐induced dilation significantly in coronary arterioles of WT mice (P<0.01 EX vs. SED), but decreased flow‐induced dilation in coronary arterioles from AdipoKO mice. ACh‐induced dilation was reduced in coronary arterioles from AdipoKO mice as compared to those from WT mice (P<0.05 AdipoKO vs. WT). Exercise training reduced ACh‐induced dilation in arterioles from WT mice, but increased ACh‐induced dilation in arterioles from AdipoKO mice. Baseline capillarity increased in the soleus muscle of AdipoKO mice as compared to WT mice, but an exercise training‐induced increase in capillarity, detected in WT mice, was absent in AdipoKO mice. Contractile responsiveness to phenylephrine was increased in arterioles from the soleus muscle of both WT and AdipoKO mice (P<0.01 EX vs. SED in both WT and AdipoKO). These data indicate that adiponectin is a critical contributor to exercise training‐induced vascular adaptations; however, locally produced adiponectin may be more critical than circulating adiponectin in mediating these adaptations.Support or Funding InformationFlorida State University College of MedicineThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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The risk for diastolic dysfunction increases with advancing age. We tested the hypotheses that 1) microvascular dysfunction underlies age‐related diastolic dysfunction, and 2) exercise training (ET) reverses age‐related microvascular and diastolic dysfunction. Old and young male Fischer 344 rats underwent 10 weeks of daily ET or remained sedentary cage controls. Cardiac function was assessed before and after ET. At the end of training, coronary blood flow was measured at rest and during treadmill exercise. The reactivity of the coronary resistance vasculature was assessed in isolated coronary arterioles. E/a ratio decreased with age and was partially restored by ET. Isovolumic relaxation time increased with age and this increase was reversed by ET. Resting blood flow to the left ventricular (LV) endocardium and the right ventricular free wall was decreased in old rats; however, ET increased resting blood flow to the septum, papillary muscles, LV endocardium and epicardium. Exercise hyperemia was reduced by age in the septum, and the LV endocardium and epicardium, but these age‐related reductions were reversed by ET. Age‐induced impairments of both contractile and relaxation responses of coronary arterioles were reversed by ET. Thus, microvascular dysfunction contributes to development of diastolic dysfunction with advancing age; however, ET at an advanced age reverses microvascular dysfunction and improves diastolic function.
Objective: The stroke-prone spontaneously hypertensive (SHRSP) rat is a model of chronic hypertension and defective vascular remodelling during pregnancy that can be stressed by administration of angiotensin II (ANGII) to mimic super-imposed pre-eclampsia. This novel model has been tested with doses of 500 ng/kg/min and 1000 ng/kg/min ANGII. The aim of this study was to characterise the pathology of this model with a dose of 750 ng/kg/min to enhance reproducibility and refine the model. Design and method: SHRSP and normotensive Wistar Kyoto (WKY) females were time mated with males of the relevant strain. On gestational day (GD) 10.5 mini osmotic pumps were implanted administering either 0.9% saline or 750 ng/kg/min of ANGII. SHRSPs were split into either SHAM (saline) or ANGII groups. WKY received saline only. At pre-pregnancy (PP), GD 6.5, 14.5 and 18.5 blood pressure, cardiac function and uteroplacental blood flow were measured by tail cuff plethysmography and ultrasound. Urine was collected by metabolic cage at PP, GD6.5 & 18.5 to assess proteinuria. Results: ANGII showed reduced pregnancy-related weight gain vs WKY and SHAM (168.3 ± 3.7 g vs 231.2 ± 3.0 g vs 183.3 ± 5.9 g, p < 0.001). ANGII showed an increased BP when compared to SHAM and WKY (180.9 ± 9.7mmHg vs 127.5 ± 6.5mmHg vs 139.8 ± 7.1 mmHg p < 0.001 GD18.5). ANGII dams showed signs of left ventricular cardiac dysfunction with an elevated relative wall thickness and reduced stroke volume and cardiac output vs WKY (p < 0.05). ANGII and SHAM exhibited impaired uteroplacental blood flow vs WKY at GD18.5 (0.57 ± 0.03au vs 0.62 ± 0.05au vs 0.38 ± 0.02au, p < 0.01). Infusion of ANGII successfully induced proteinuria, measured as urinary albumin:creatinine compared to SHAM and WKY (12.2 ± 8.28 μg/μmol/L vs 0.16 ± 0.01 μg/μmol/L vs 3.9 ± 0.40 μg/μmol/L, p < 0.001). Conclusions: The results presented here show this model has effectively captured the overall disease picture of pre-eclampsia with consistent disease characteristics such as proteinuria, hypertension, maternal cardiovascular impairment and dysregulated uterine artery remodelling. It may serve as a useful tool in the study of pre-eclampsia.
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