Transcriptomic Profiling of the Sex-linked Biological Pathways of Severe Pulmonary Arterial Hypertension associated with Endothelial Cell Caveolin-1 Depletion and Chronic Hypoxia

Both female and male CAV1-/- mice in chronic hypoxia demonstrated elevated right ventricular systolic pressure (RVSP) of 48.49mmHg and 47.78mmHg respectively. Female knockout mice started to die earlier in hypoxic conditions (4 wks), though male mice showed greater total mortality by the end of the 8 wks of hypoxia. In addition to wildtype controls, we compared this knockout mouse to endothelial-specific CAV1 reconstituted (CAV1-RC) knockouts and found that restoration of CAV1 expression only in endothelial cells (ECs) is sufficient to ameliorate PAH symptoms, highlighting the importance of vascular CAV1 in maintaining pulmonary artery function.

RNA-sequencing of the lungs revealed that CAV1-/- is associated with downregulation of biological process gene pathways involved in cilium assembly in normoxic conditions for both sexes. In hypoxic conditions, CAV1 knockout in females leads to downregulation of BMP signaling, while male hypoxic CAV1-/- led to a significant increase in muscle cell development genes. Reconstitution of CAV1 in ECs lead to upregulation of immune signaling pathways, muscle cell development, and various cell differentiation pathways in both sexes.

Females showed a unique upregulation of cilia-related pathways, while males demonstrated increased BMP signaling. These data indicate that muscle cell development, angiogenesis, cilia assembly, immune response, and BMP signaling pathways undergo sex-specific transcriptional regulation during PH development that may underlie sex differences in PH patient outcome.