ABSTRACT Pulmonary arterial hypertension (PAH) is a chronic lung disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure and death. The incidence of PAH is much higher in female patients (4:1 ratio). While previous studies investigating sex differences in PAH have focused extensively on the role of gonadal hormones, in particular estrogen, we are the first lab to investigate the role of sex chromosomes in PAH. Our recent published work using innovative mouse models demonstrated in the absence of sex hormones, the Y chromosome (ChrY) protects against experimental pulmonary hypertension (PH), indicating that gene(s) encoded on ChrY can protect against PH. Only 4 genes on ChrY are expressed in the lungs Uty, Kdm5d, Eif2s3y, and Ddx3y. Our preliminary data identified Uty as the top candidate gene responsible for ChrY protection against PH. Additionally, we demonstrate that Uty expression is reduced in male patients with PAH and multiple animal models of PH. Our RNAseq analysis on the lungs of PH wildtype (WT) and Uty-KD male mice revealed a few promising targets including the proinflammatory cytokines Cxcl9 and Cxcl10. Our preliminary data shows Uty co-localizes with Cxcl9/10 in lung macrophages, and expression of Cxcl9/10 is significantly increased in bone marrow derived macrophages isolated from Uty global KO mice compared to WT. More importantly, our pilot study shows that blocking the shared Cxcl9/10 receptor, Cxcr3, using AMG487 can reduce PH severity in female rats with PH. Our bioinformatics analysis also identified Endothelin-2 (ET-2) is up-regulated in the lung as a result of Uty-KD. The role of ET-2 is currently unknown in PAH. For the first time, we show that increased ET-2 expression may contribute to worsening PH by inhibiting angiogenesis and promoting SMC proliferation in the lung. Our working hypotheses are: (1) ChrY gene Uty protects against PH development; (2) loss or absence of Uty results in more severe PH through increased expression of Cxcl9/10 and ET-2 resulting in vascular EC death, SMC proliferation and pathological angiogenesis; and (3) Blocking Cxcl9/10 alone or together with blocking ET-2 activity reduces the severity of PH in a sex-specific manner. Aim 1. To examine whether knockdown of Uty in the lungs, in the presence and absence of hormones, abolishes the protective role of ChrY in experimental PH; Aim 2. Investigate the mechanistic role of the Uty/Cxcl9/10 and Uty/ET-2 axes in PH pathogenesis; Aim 3. Determine if blocking the activity of downstream Uty genes Cxcl9/10 alone or together with blocking ET-2 rescues PH development by reducing EC apoptosis and SMC proliferation and promoting angiogenesis in male and female rats.