Newer insights into the pathobiological and pharmacological basis of the sex disparity in patients with pulmonary arterial hypertension

Author:

Hye Tanvirul1,Dwivedi Pankaj2,Li Wei3,Lahm Tim456,Nozik-Grayck Eva7ORCID,Stenmark Kurt R.7,Ahsan Fakhrul18

Affiliation:

1. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Abilene, Texas

2. Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in St. Louis, St. Louis, Missouri

3. Department of Chemical Engineering, Texas Tech University, Lubbock, Texas

4. Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana

5. Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana

6. Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana

7. Department of Pediatrics and Medicine, Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado

8. Department of Pharmaceutical and Biomedical Sciences, California Northstate University, Elk Grove, California

Abstract

Pulmonary arterial hypertension (PAH) affects more women than men, although affected females tend to survive longer than affected males. This sex disparity in PAH is postulated to stem from the diverse roles of sex hormones in disease etiology. In animal models, estrogens appear to be implicated not only in pathologic remodeling of pulmonary arteries, but also in protection against right ventricular (RV) hypertrophy. In contrast, the male sex hormone testosterone is associated with reduced survival in male animals, where it is associated with increased RV mass, volume, and fibrosis. However, it also has a vasodilatory effect on pulmonary arteries. Furthermore, patients of both sexes show varying degrees of response to current therapies for PAH. As such, there are many gaps and contradictions regarding PAH development, progression, and therapeutic interventions in male versus female patients. Many of these questions remain unanswered, which may be due in part to lack of effective experimental models that can consistently reproduce PAH pulmonary microenvironments in their sex-specific forms. This review article summarizes the roles of estrogens and related sex hormones, immunological and genetical differences, and the benefits and limitations of existing experimental tools to fill in gaps in our understanding of the sex-based variation in PAH development and progression. Finally, we highlight the potential of a new tissue chip-based model mimicking PAH-afflicted male and female pulmonary arteries to study the sex-based differences in PAH and to develop personalized therapies based on patient sex and responsiveness to existing and new drugs.

Funder

HHS | NIH | National Heart, Lung, and Blood Institute

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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