Mice with targeted deletion of the Vasoactive Intestinal Peptide (VIP) gene have spontaneous pulmonary arterial hypertension exaggerated with hypoxia

We earlier reported spontaneous moderate pulmonary arterial hypertension in Vasoactive Intestinal Peptide (VIP) gene knockout mice. In the current study, we show accelerated pulmonary artery pressure changes associated with vascular and cardiac remodeling changes in VIP KO mice subjected to hypoxia compared to control wild-type C57BL/6 mice in hypoxia chambers. There is differential whole-lung RNA sequencing expression between baseline normoxia wild-type and VIP KO mice groups. Under conditions of hypoxia vs. normoxia, we observe upregulation of spatial biology expression of CD45 in VIP KO mice with hypoxia, but not in wild-type mice with hypoxia. Moreover, wild-type hypoxia mice express alpha-actin and CD31, which is not seen in the VIP KO hypoxia cohort. Human lung tissue from pediatric patients with idiopathic pulmonary arterial hypertension (PAH) lacks immunohistochemical evidence of VIP, supporting the concepts that VIP plays a critical role in the immunopathogenesis of pulmonary hypertension and VIP or its analogues may potentially be used to treat PAH.