Nbeal2 knockout mice are not protected against hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension

Inflammation drives the initiation and progression of pulmonary hypertension (PH). Platelets, increasingly recognized as immune cells, are activated and increased in the lungs of patients with PH. Platelet activation leads to the release of α-granule chemokines, many of which are implicated in PH. We hypothesized that hypoxia-induced secretion of platelet α-granule–stored proteins and PH would be prevented in Neurobeachin-like 2 knockout (Nbeal2⁻/⁻) α-granule–deficient mice. Wild-type (WT) and Nbeal2⁻/⁻ mice were maintained in normoxia or exposed to 10% hypobaric hypoxia for 3, 14, 21, or 35 days. We observed macrothrombocytopenia, increased circulating neutrophils and monocytes, and increased lung interstitial macrophages (IMs) in Nbeal2⁻/⁻ mice at baseline. Hypoxia-induced platelet activation was attenuated, and hypoxia-induced increase in lung platelet factor 4 (PF4) and platelets was delayed in Nbeal2⁻/⁻ mice compared with in WT mice. Finally, although pulmonary vascular remodeling (PVR) and PH were attenuated at day 21, Nbeal2⁻/⁻ mice were not protected against hypoxia-induced PVR and PH at day 35. Although this mutation also affected circulating monocytes, neutrophils, and lung IMs, all of which are critical in the development of experimental PH, we gained further support for the role of platelets and α-granule proteins, such as PF4, in PH progression and pathogenesis and made several observations that expand our understanding of α-granule–deficient mice in chronic hypoxia.