At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2020 Nov 25

PMID 33233517

Citations 5

Authors

Meghan M Cirulis

Mark W Dodson

Lynn M Brown

Samuel M Brown

Tim Lahm

Greg Elliott

Affiliations

Soon will be listed here.

Abstract

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

Citing Articles

[Protective effects of 2-methoxyestradiol against hypoxic pulmonary hypertension in neonatal rats].

Xie O, Li S, Luo Y, Wang L Zhongguo Dang Dai Er Ke Za Zhi. 2024; 26(7):757-764.

PMID: 39014954 PMC: 11562046. DOI: 10.7499/j.issn.1008-8830.2401078.

Sex-biased TGFβ signalling in pulmonary arterial hypertension.

Wits M, Becher C, de Man F, Sanchez-Duffhues G, Goumans M Cardiovasc Res. 2023; 119(13):2262-2277.

PMID: 37595264 PMC: 10597641. DOI: 10.1093/cvr/cvad129.

Metabolic reprogramming, oxidative stress, and pulmonary hypertension.

Pokharel M, Marciano D, Fu P, Franco M, Unwalla H, Tieu K Redox Biol. 2023; 64:102797.

PMID: 37392518 PMC: 10363484. DOI: 10.1016/j.redox.2023.102797.

Pulmonary Arterial Hypertension: A Deeper Evaluation of Genetic Risk in the -Omics Era.

Machado R, Southgate L Genes (Basel). 2021; 12(11).

PMID: 34828405 PMC: 8619860. DOI: 10.3390/genes12111798.

Sex and gender in pulmonary arterial hypertension.

Cheron C, McBride S, Antigny F, Girerd B, Chouchana M, Chaumais M Eur Respir Rev. 2021; 30(162).

PMID: 34750113 PMC: 9488668. DOI: 10.1183/16000617.0330-2020.

References

Dubey R, Gillespie D, Zacharia L, Rosselli M, Korzekwa K, Fingerle J . Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms. Biochem Biophys Res Commun. 2000; 278(1):27-33. DOI: 10.1006/bbrc.2000.3755. View

Dougherty S, Mazhawidza W, Bohn A, Robinson K, Mattingly K, Blankenship K . Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocr Relat Cancer. 2006; 13(1):113-34. PMC: 1472635. DOI: 10.1677/erc.1.01118. View

Hester J, Ventetuolo C, Lahm T . Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure. Compr Physiol. 2019; 10(1):125-170. PMC: 7338988. DOI: 10.1002/cphy.c190011. View

Wang G, Fan R, Ji R, Zou W, Penny D, Varghese N . Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report. BMC Pulm Med. 2016; 16:17. PMC: 4722683. DOI: 10.1186/s12890-016-0183-7. View

Muti P, Bradlow H, Micheli A, Krogh V, Freudenheim J, Schunemann H . Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000; 11(6):635-40. DOI: 10.1097/00001648-200011000-00004. View

Nadadur R, Umar S, Wong G, Eghbali M, Iorga A, Matori H . Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension. J Appl Physiol (1985). 2012; 113(1):149-58. PMC: 3404831. DOI: 10.1152/japplphysiol.01349.2011. View

Chen N, Collum S, Luo F, Weng T, Le T, Hernandez A . Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2016; 311(2):L238-54. PMC: 6425517. DOI: 10.1152/ajplung.00142.2016. View

Yang J, Li X, Morrell N . Id proteins in the vasculature: from molecular biology to cardiopulmonary medicine. Cardiovasc Res. 2014; 104(3):388-98. DOI: 10.1093/cvr/cvu215. View

Yan L, Cogan J, Hedges L, Nunley B, Hamid R, Austin E . The Y Chromosome Regulates BMPR2 Expression via SRY: A Possible Reason "Why" Fewer Males Develop Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2018; 198(12):1581-1583. PMC: 6298637. DOI: 10.1164/rccm.201802-0308LE. View

10.

Cogan J, Pauciulo M, Batchman A, Prince M, Robbins I, Hedges L . High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006; 174(5):590-8. PMC: 2648061. DOI: 10.1164/rccm.200602-165OC. View

11.

Ventetuolo C, Ouyang P, Bluemke D, Tandri H, Barr R, Bagiella E . Sex hormones are associated with right ventricular structure and function: The MESA-right ventricle study. Am J Respir Crit Care Med. 2010; 183(5):659-67. PMC: 3081282. DOI: 10.1164/rccm.201007-1027OC. View

12.

Fishman J, Martucci C . Biological properties of 16 alpha-hydroxyestrone: implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab. 1980; 51(3):611-5. DOI: 10.1210/jcem-51-3-611. View

13.

Aldred M, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez M, Martensson G . BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat. 2006; 27(2):212-3. DOI: 10.1002/humu.9398. View

14.

Ge X, Zhu T, Zhang X, Liu Y, Wang Y, Zhang W . Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis. Respir Res. 2020; 21(1):44. PMC: 7006426. DOI: 10.1186/s12931-020-1309-2. View

15.

Chen X, Talati M, Fessel J, Hemnes A, Gladson S, French J . Estrogen Metabolite 16α-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II-Associated Pulmonary Arterial Hypertension Through MicroRNA-29-Mediated Modulation of Cellular Metabolism. Circulation. 2015; 133(1):82-97. PMC: 4698046. DOI: 10.1161/CIRCULATIONAHA.115.016133. View

16.

Austin E, Loyd J, Phillips 3rd J . Genetics of pulmonary arterial hypertension. Semin Respir Crit Care Med. 2009; 30(4):386-98. PMC: 3737593. DOI: 10.1055/s-0029-1233308. View

17.

Swift A, Capener D, Hammerton C, Thomas S, Elliot C, Condliffe R . Right ventricular sex differences in patients with idiopathic pulmonary arterial hypertension characterised by magnetic resonance imaging: pair-matched case controlled study. PLoS One. 2015; 10(5):e0127415. PMC: 4440634. DOI: 10.1371/journal.pone.0127415. View

18.

Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R . A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet. 2009; 46(5):331-7. DOI: 10.1136/jmg.2008.062703. View

19.

Gajjar K, Martin-Hirsch P, Martin F . CYP1B1 and hormone-induced cancer. Cancer Lett. 2012; 324(1):13-30. DOI: 10.1016/j.canlet.2012.04.021. View

20.

Simoncini T, Hafezi-Moghadam A, Brazil D, Ley K, Chin W, Liao J . Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000; 407(6803):538-41. PMC: 2670482. DOI: 10.1038/35035131. View