Choose Your Maternal DNA Wisely: Intrinsic Exercise Capacity and Mitochondrial Genome Influence Vascular Function in Rats

“Choose your parents wisely” is a popular adage coined by the British Philosopher Bertrand Russell, and often used when discussing issues such as socioeconomic position and genetic contributions to disease risk. When it comes to vascular function, a predictor of cardiovascular disease risk, the recent study in Function by Roy et al. extends the adage to “choose our maternal mitochondrial DNA wisely. ” The study characterized vascular function in rats with a low capacity for running (LCR) and high capacity for running (HCR). Aerobic exercise is a positive health behavior for the prevention and treatment of cardiovascular and metabolic disease states. Aerobic exercise training generally leads to improved cardiorespiratory fitness (CRF), but genetic predispositions for intrinsic capacity and trainability lead to substantial variability. Importantly, CRF is a predictor of cardiovascular and all-cause mortality. Moreover, resistance artery dysfunction precedes end-organ damage from hypertension and cardiovascular disease. Thus, the authors sought to determine whether CRF influences resistance artery structure and function, cardiac function, perivascular adipose tissue (PVAT), and bioenergetic profiling in vascular cells. Moreover, the researchers sought to determine whether the inherited mitochondrial genome associated with intrinsic exercise capacity also independently influences vascular physiology. The investigators studied rats artificially selected (withinfamily) for intrinsic aerobic endurance running capacity to generate LCR and HCR male rats. As previously described, the authors also generated conplastic strains, whereby LCR male rodents were bred with mitochondrial DNA (mtDNA) of female HCR rodents (LCR-mt) and vice versa (HCR-mt). Specifically, HCR female offspring were backcrossed with male LCR (or the reciprocal) via inbreeding, and this backcross procedure was repeated over several generations to generate the LCR-mt and HCR-mt. The investigators performed echocardiography to assess cardiac function and left ventricular mass, wire, and pressure myography to assess arterial vasodilatory function (with and without PVAT) and mechanics, macroscopic tissue imaging of PVAT, and bioenergetic assays with vascular smooth muscle cells (VSMCs). Compared to HCR, LCR rats had higher body mass, epididymal fat mass, and blood pressure. Regarding cardiac measures, HCR rats presented higher left ventricular mass than LCR rats (see Figure 1). Compared to LCR, HCR rats exhibited lower relative ventricular wall thickness and fractional area change, a surrogate of systolic function, but no differences were observed for multiple measures of cardiac output, velocity of circumferential fiber shortening, or myocardial contractility. Interestingly, mitochondrial swap increased left ventricular mass in LCR (ie, " in LCR-mt) but decreased left ventricular mass and several indices of cardiac performance in HCR-mt relative to HCR. The key findings were that compared to HCR, LCR rats presented with lower endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilation in mesenteric resistance arteries. Mitochondrial swap rescued endothelium-dependent and endothelium-independent vasodilation in LCR (" in LCR-mt), however, it did not reduce vascular function in HCR-mt. Using mesenteric arterioles and plotting internal lumen and external diameters with intraluminal pressure curves, the authors revealed that the