Seelemann Erica R, Panchakshari Sheethal, Labana Parabhjot Kaur, Wolverton Maxwell M, Deng Yupu, Abdelwahab Haya, Consmueller Chris, Stewart Duncan J, Chaudhary Ketul R
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Am J Physiol Heart Circ Physiol. 2025 Mar 1;328(3):H496-H508. doi: 10.1152/ajpheart.00549.2024. Epub 2025 Jan 28.
This study investigated the sexual dimorphism in right ventricle (RV) remodeling in right heart failure susceptible Fischer CDF rats using the pulmonary artery banding (PAB) model. Echocardiography and hemodynamic measurements were performed in adult male and female Fischer CDF rats at 1- or 2-wk post-PAB. RV systolic pressure and RV hypertrophy were significantly elevated in PAB rats compared with sham control at 1- and 2-wk post-PAB; however, no differences were observed between male and female rats. Increase in cardiomyocyte cross-sectional area and RV end-diastolic diameter was observed in male rats compared with female rats at 2-wk post-PAB. Conversely, higher fractional area change and cardiac index were observed in female rats compared with male rats at 2-wk post-PAB. To explore the mechanisms, a focused PCR array was performed and higher expression of angiogenic genes, including sphingosine kinase-1 (), was observed in the RV of female rats compared with male rats. Consistent with the higher angiogenic gene expression, female rats had a higher RV vascular density at 2-wk post-PAB compared with male rats. Female RV endothelial cells (RVECs) had better angiogenic ability compared with male cells that was potentiated by estradiol. Furthermore, effect of estradiol on RVECs was inhibited by Sphk1 inhibitor (PF-543). Together, female Fischer CDF rats develop adaptive RV remodeling post-PAB compared with maladaptive remodeling in male rats. Moreover, the adaptive remodeling in female rats is associated with better RV angiogenic response that may result from better angiogenic ability of female RVECs and proangiogenic effects of estradiol through Sphk1. Female patients with pulmonary hypertension have better right ventricular adaptation compared with male. These sex differences were modeled in right heart failure susceptible Fischer CDF rat using pulmonary artery banding model. Preservation of right ventricular function in female rats is linked to better right ventricular angiogenic response that involves higher intrinsic angiogenic ability of female right ventricular endothelial cells together with the proangiogenic effects of female sex hormone estradiol through sphingosine kinase-1.
本研究使用肺动脉环扎（PAB）模型，调查了易患右心衰竭的Fischer CDF大鼠右心室（RV）重塑中的性别差异。在成年雄性和雌性Fischer CDF大鼠PAB术后1周或2周进行超声心动图和血流动力学测量。与假手术对照组相比，PAB大鼠在PAB术后1周和2周时RV收缩压和RV肥厚显著升高；然而，雄性和雌性大鼠之间未观察到差异。与雌性大鼠相比，在PAB术后2周时观察到雄性大鼠心肌细胞横截面积和RV舒张末期直径增加。相反，在PAB术后2周时，与雄性大鼠相比，雌性大鼠的面积变化分数和心脏指数更高。为了探索其机制，进行了聚焦PCR阵列分析，与雄性大鼠相比，在雌性大鼠的RV中观察到血管生成基因（包括鞘氨醇激酶-1）的更高表达。与更高的血管生成基因表达一致，与雄性大鼠相比，雌性大鼠在PAB术后2周时RV血管密度更高。与雄性细胞相比，雌性RV内皮细胞（RVECs）具有更好的血管生成能力，且这种能力被雌二醇增强。此外，鞘氨醇激酶1抑制剂（PF-543）可抑制雌二醇对RVECs的作用。总之，与雄性大鼠的适应性不良重塑相比，雌性Fischer CDF大鼠在PAB术后发生适应性RV重塑。此外，雌性大鼠的适应性重塑与更好的RV血管生成反应相关，这可能是由于雌性RVECs更好的血管生成能力以及雌二醇通过鞘氨醇激酶1产生的促血管生成作用。与男性相比，患有肺动脉高压的女性患者右心室适应性更好。这些性别差异在易患右心衰竭的Fischer CDF大鼠中使用肺动脉环扎模型进行了模拟。雌性大鼠右心室功能的保留与更好的右心室血管生成反应有关，这涉及雌性右心室内皮细胞更高的内在血管生成能力以及雌性性激素雌二醇通过鞘氨醇激酶-1产生的促血管生成作用。
