Mending sex differences: Unravelling the female predominance in pulmonary hypertension

Introduction

Pulmonary hypertension (PH) is a rare but progressive fatal disease characterized by the accumulation of persistently activated cell types in the pulmonary vascular wall, exhibiting abnormal expression of genes driving proliferation, inflammation, and metabolism. The currently used vasodilatory therapies have little or no impact on this activated phenotype and therefore offer no cure or even substantial survival benefit. PH has a high female predominance (3:1 to 9:1). This proposal aims to understand the mechanism behind the high female predominance to identify novel therapeutic targets to attenuate disease progression in male and female PH patients.

Mechanisms of Female Predominance

Female predominance can be linked to sex hormones and/or incomplete X chromosome inactivation (XCI), leading to biallelic expression of immunoinflammatory and metabolic genes.

Research Approach

To understand the impact of oestrogen and androgen signalling on abnormal vascular remodelling in PH, I will:

1. Develop a unique opposite-sex lung transplantation rat model.
2. Identify oestrogen metabolites in a large set of patient serum samples.
3. Explore their biological relevance using pulmonary vascular cells from male and female PH patients in cell-based assays.

Preliminary experiments suggest there is incomplete XCI in PH.

Characterization of Incomplete XCI

I propose to combine sequencing and molecular studies to extensively characterize the impact of incomplete XCI on the physiology of male and female PAH cells. This will involve identifying genes and druggable targets regulating incomplete XCI in PH.

Novel Drug Delivery Method

Finally, I will explore a novel pulmonary endothelium-specific drug delivery method to deliver identified promising genes/compounds to selectively inhibit the activated pulmonary vasculature, thereby minimizing side effects compared to current delivery methods.

Conclusion

Together, this high risk-high gain study will dissect the molecular mechanisms underlying the unresolved female predominance in PH and offer novel pulmonary endothelium-specific therapies for both male and female PH patients.