Abstract Body: Introduction
Maternal obesity is a major risk factor for pregnancy-related cardiovascular disease (CVD), including preeclampsia and peripartum cardiomyopathy (PPCM). Placental senescence and its senescence-associated secretory phenotype (SASP) are implicated in the shared pathophysiology underlying PPCM and preeclampsia. How maternal obesity contributes to this shared pathophysiology is unclear.
Hypothesis
Maternal obesity increases placental senescence and contributes to the common endothelial cell (EC) dysfunction phenotype in pregnancy-related CVD.
Methods
A high fat diet (HFD)-induced maternal obesity mouse model was used. Obese vs non-obese pregnant and nonpregnant C57BL/6 mice underwent tail cuff blood pressure and echocardiography assessments before pregnancy (not pregnant, NP) and late pregnancy (GD15) (n=5). Placental senescence was assessed in pregnant mice at GD17. To gain mechanistic insights into how the senescent placental secretome regulates EC function, human umbilical vein endothelial cells (HUVEC) were exposed to conditioned media (CM) from ex vivo cultured placentas from obese vs nonobese mice.
Results
Systolic blood pressure increased by ~16% in obese GD15 mice compared to non-pregnant mice (99.6 +/ 16.1 mmHg vs 109.0 +/21.2 mmHg, p=0.07). Pregnancy also induced cardiac hypertrophy (LV mass: 89 g/m² vs 117.1 g/m², p=0.1) and dysfunction (%fractional shortening: 42.3 +/1.7% vs 30.5 +/5.6%, p=0.01) in obese vs control C57BL/6J females. Notably, obese pregnant mice also displayed evidence of increased placental senescence compared to non-obese pregnant controls, indicated by increased protein expression of p16 (FC 1.9, p=0.07) and Pai-1 (FC 2.4, p=0.04). Conditioned medium from ex vivo cultured placentas from obese vs non-obese pregnant mice induced a pro-senescent and pro-inflammatory transcriptional profile in HUVECs, including increased Cdkn2a (FC 1.8, p=0.1), Cdkn1a (FC 1.6, p=0.004), Serpine1 (FC 1.3, p=0.04), and Icam1 (FC 1.3, p=0.2) expression.
Discussion/Conclusion
Maternal obesity is associated with increased placental senescence and a SASP that promotes paracrine EC senescence, which could contribute to increased pregnancy-related CVD risk.