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. These cells exhibit 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.

Female Predominance

PH has a high female predominance, with ratios ranging from 3:1 to 9:1. This proposal aims to understand the mechanism behind this high female predominance to identify novel therapeutic targets to attenuate disease progression in both male and female PH patients.

Mechanisms Behind Female Predominance

Female predominance can be linked to:

• Sex hormones
• Incomplete X chromosome inactivation (XCI) leading to biallelic expression of immunoinflammatory and metabolic genes

Research Objectives

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

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

Preliminary experiments suggest there is incomplete XCI in PH. 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 include 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. This method aims 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.