D106-07 Early Pulmonary Vascular and Alveolar Impairment in Bmpr2 Mutant Rats Drives the Development of Later Pulmonary Hypertension

Abstract Background Intrauterine growth restriction (IUGR) impairs alveolar and pulmonary vascular development, increasing the risk of neonatal pulmonary hypertension (PH). Bone morphogenetic protein receptor type 2 (BMPR2) mutation, a well-known genetic risk for pulmonary arterial hypertension (PAH), also disrupts vascular and airway development. We hypothesized that Bmpr2 mutation exacerbates pulmonary hemodynamic abnormalities and lung structural changes in IUGR rats induced by maternal nitric oxide synthase inhibition (L-NAME). Methods Wild-type (WT) pregnant rats mated with Bmpr2 mutant male rats received either vehicle (control) or L-NAME via osmotic pump from gestational day 17. Offspring were assigned to four groups : control/WT, control/mutant, L-NAME/WT and L-NAME/mutant. Body weight (BW), pulmonary hemodynamics, lung histology, and molecular analyses were evaluated at postnatal day (P)2 (n = 64 males, 62 females), at 7 weeks of age (n = 89, 74), and in three experimental models of PAH: monocrotaline (MCT), chronic hypoxia (CH), and SU5416/hypoxia (n = 40, 38, 36, males, respectively). Results At P2, L-NAME/mutant rats exhibited more severe vascular and alveolar injury than L-NAME/WT, with decreased vascular density (1.2 ± 0.75 vs. 3.1 ± 0.53; P.05), higher mean linear intercept (107 ± 15 vs. 92 ± 9.5; P.05), and a trend toward lower body weight (7.0 ± 1.3 g vs. 7.2 ± 1.0 g). Type II alveolar epithelial cells were reduced, showing decreased proliferation and increased apoptosis in L-NAME/mutant (P.05). The alveolar capillary endothelial cell marker Car4 was upregulated (P.05), whereas apelin expression was decrease (P.05). Lung BMPR2 expression was reduced in L-NAME/WT compared with control/WT (P.01) and further decreased in L-NAME/mutant (P.005). At 7 weeks, mutant rats exhibited more severe L-NAME-induced IUGR than WT (188 ± 36 g vs 215 ± 21; P.05), with worsened alveolar simplification (58 ± 8.7 vs 48 ± 6.4; P.05) and increased macrophage infiltration (P.05). L-NAME groups showed higher right ventricular systolic pressure (RVSP) and greater distal pulmonary arteries muscularization than control (P.05) similarly in both WT and mutant. In the three PAH models, L-NAME/mutant rats developed the most severe PH and vascular remodeling: RVSP 55 ± 6.0 mmHg vs 49 ± 5.8 in MCT, 59 ± 3.6 vs 53 ± 3.0 in CH, and 100 ± 14 vs 90 ± 16 in SU5416/hypoxia (P.05). Conclusion Bmpr2 mutation synergistically exacerbates alveolar and vascular maldevelopment following perinatal insults, contributing to the progression of late-onset PH. These findings highlight the vulnerability of Bmpr2 mutants to perinatal insult and warrant the importance of BMPR2 signaling in long-term cardiopulmonary sequelae. This abstract is funded by: kakenhi24k12600