UCLA

Pulmonary arterial hypertension is a rare but terminal pulmonary vascular disease characterized by elevated pressure in the pulmonary circulation coupled with right ventricular hypertrophy and failure. This disease is up to four times more common in women—a striking sex difference that cannot be explained by the contributions of sex hormones alone. This dissertation is a compilation of the first work investigating the sex biasing contributions of sex chromosomes in pulmonary arterial hypertension.

In Chapter 2, we use powerful mouse models to identify the male-specific Y chromosome confers protection against the development of experimental pulmonary hypertension. In Chapter 3, we use a combination of experimental models and bioinformatic approaches to identify the gene on the Y chromosome that protects males against the development of pulmonary hypertension and its downstream effector genes. We found the Y chromosome gene Uty protects against the development of pulmonary hypertension by attenuating a proinflammatory lung response. Loss or lack of Uty gene expression results in an elevated inflammatory response that contributes detrimentally to disease severity. We identified two chemokines, Cxcl9 and Cxcl10, that are downstream of and inversely related to Uty as particularly harmful in pulmonary hypertension. We show that blocking their activity is sufficient to extend Y chromosome protection to females in a novel, preclinical therapy. In Chapter 4, we expand on our findings of downstream Uty effector genes and identify a sex-specific upregulation of Endothelin-2 that is linked to loss of Uty expression and elevated Cxcl9 and Cxcl10 levels. While the role of Endothelin-1 is known in pulmonary hypertension, the role of Endothelin-2, a proinflammatory and vasoconstrictive peptide, has not yet been studied. Our findings regarding Endothelin-2 help explain a clinical sex difference in the efficacy of endothelin receptor antagonist therapies for pulmonary hypertension where females are more responsive to treatment.

Taken together, this dissertation offers evidence of a powerful sex-biasing Y chromosome effect in pulmonary hypertension, elucidates novel therapeutic approaches for the treatment of this terminal disease, and serves as an example of the translational relevance in investigating sex differences in disease. While the studies presented provide the first insight into the role of sex chromosomes in pulmonary hypertension, they also provide a foundation for further examination which are highlighted here as future directions.