Background and objective: Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the distal pulmonary arteries, ultimately leading to right heart failure and, despite the available therapeutics, survival remains poor. Reduced expression of bone morphogenetic protein receptor type 2 (BMPR2) is strongly associated with PAH. Cell therapies are of interest in PAH, but whether this approach can upregulate BMPR2 is not known. Our objective was to evaluate a preclinical cell therapy approach based on upregulation of BMPR2. Methods: We assessed the therapeutic effect of intravenously injected BMPR2-augmented rat bone marrowderived endothelial-like progenitor cells (BMPR2-BM-ELPC) on PAH in the rat monocrotaline (MCT) model. Results: The cells accumulate in the lungs with negligible systemic distribution, but the vast majority are lost from the lungs by 24 h. Lungs from rats treated with BMPR2-BM-ELPC exhibited an immediate increase in BMPR2 and related intracellular signalling proteins. Treatment with BMPR2-BM-ELPC attenuated PAH as demonstrated by a reduction in right ventricular hypertrophy as well as right ventricular systolic and mean pulmonary arterial pressures. In addition, this treatment reversed PAH-induced vascular remodelling with a significant reduction in vessel thickness and muscularization. In view of the short retention time of injected cells in the lungs, the mechanism for the effects seen may be intracellular communication via exosomes. In support of this hypothesis, we demonstrate that BMPR2-transduced outgrowth endothelial progenitor cells (OECs) release BMPR2-expressing exosomes. Conclusion: BMPR2-augmented ELPC demonstrate therapeutic benefits in the rat model and may have clinical translation potential.Pulmonary arterial hypertension (PAH) is causally linked to reduced bone morphogenetic protein receptor type 2 (BMPR2) expression. Endothelial progenitor cells engineered to overexpress BMPR2 are therapeutic in the rat monocrotaline PAH model, despite short retention time in the lungs. This approach may have clinical potential.

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The physiology and behavior of gilts that develop in a male-biased litter can differ from gilts that develop in a female-biased litter. We hypothesized that gilts from male-biased litters will have a delayed and attenuated luteinizing hormone (LH) surge, and reduced LH pulse frequency and amplitude compared to gilts from female-biased litters. Gilts were selected at birth from male-biased (>60% males n = 10) or female-biased (>60% females n = 9) litters. From 18 wk of age, detection of puberty using daily boar contact began and their subsequent estrous periods were synchronized with oral progestogen (altrenogest). On day 3 after altrenogest withdrawal, blood samples were obtained from 6 gilts per sex bias group at 10 min intervals from 0900 to 2100 h to determine LH pulse amplitude and frequency. From 0900 on day 4, all 19 gilts were sampled every 4 h until the end of estrus to characterize LH surge dynamics. There were no differences between groups in LH pulse characteristics. Compared to gilts from female-biased litters, the LH surge in gilts from male-biased litters was delayed [56.00 ± 3.32 h vs. 43.11 ± 3.76 h (mean ± standard error of the mean (SEM)), P < 0.05], the duration was decreased [29.78 ± 2.12 h vs. 37.71 ± 1.19 h (mean ± SEM), P < 0.05] and the total secretion as measured by area under the curve was decreased (91.42 ± 9.52 ng/mL vs. 120.28 ± 9.48 ng/mL, P < 0.05). Our results indicate that a male-biased uterine environment has different effects on the tonic secretion of LH than the LH surge, with only some elements of the LH surge being affected.