Cardiovascular-specific PTH1R activation enhances exercise-induced cardiac remodeling in a mouse model of calcific...

Exercise reduces cardiovascular events, yet its interactions with parathyroid hormone (PTH) and atherosclerotic calcification as well as their combined effects on cardiac remodeling remain unclear. Thus, we tested effects of constitutive activation of the PTH type I receptor (PTH1R) with and without exercise on aortic calcification and cardiovascular remodeling in a mouse model of atherosclerotic calcification. Female Ldlr^{-/-;Tagln-PTH1R} transgenic (Tg) and Ldlr^-/- littermate control (Ctrl) mice were fed a Western diet beginning at 9-10 weeks of age. At age 40 weeks, mice were assigned to sedentary (SED) or treadmill exercise (TM) regimens for 9 weeks. MicroPET/CT and echocardiography were performed at baseline and study completion. By microCT, aortic calcium content increased in all four groups. However, ¹⁸F-NaF uptake, reflecting mineral surface area, increased only in Ctrl/TM mice. Systolic function improved and left ventricular (LV) mass decreased in Tg/TM and Ctrl/TM groups. However, in Ctrl/TM mice, LV chamber diameter increased while anterior wall thickness decreased, consistent with eccentric remodeling. In contrast, in Tg/TM mice, diastolic wall thickness decreased without chamber enlargement, indicating preserved geometry and enhanced contractile efficiency. In sedentary mice (Tg/SED and Ctrl/SED), diastolic LV diameter increased without changes in wall thickness or systolic function, consistent with ventricular remodeling due to aortic stiffening in hyperlipidemia. These findings suggest that vascular PTH1R signaling selectively modulates cardiovascular adaptation to exercise. By preserving geometry and improving contractile efficiency, PTH1R activation augments the beneficial effects of exercise on adverse cardiac remodeling in atherosclerotic calcification, supporting endocrine and exercise contributions to ventricular-vascular coupling.