Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells

Kirsty M. Mair, Xu Dong Yang, Lu Long, Kevin White, Emma Wallace, Marie-Ann Ewart, Craig K. Docherty, Nicholas W. Morrell, Margaret R. MacLean

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH). Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs). Methods: We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1. Measurements and Main Results: Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phospho-Smad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1+/-mice developed pulmonary hypertension (reversed by ovariectomy). Conclusions: We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.

LanguageEnglish
Pages693-703
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number6
DOIs
Publication statusPublished - 15 Mar 2015

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Type II Bone Morphogenetic Protein Receptors
Pulmonary Artery
Smooth Muscle Myocytes
Pulmonary Hypertension
Estrogens
Proteins
Bone and Bones
Hypertension
Messenger RNA
Platelet-Derived Growth Factor
DNA-Binding Proteins
Ovariectomy

Keywords

  • bone morphogenic protein type II
  • estrogen
  • proliferation
  • pulmonary hypertension
  • sex

Cite this

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title = "Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells",
abstract = "Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80{\%} of patients with heritable PAH (hPAH). Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs). Methods: We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1. Measurements and Main Results: Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phospho-Smad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1+/-mice developed pulmonary hypertension (reversed by ovariectomy). Conclusions: We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.",
keywords = "bone morphogenic protein type II, estrogen, proliferation, pulmonary hypertension, sex",
author = "Mair, {Kirsty M.} and Yang, {Xu Dong} and Lu Long and Kevin White and Emma Wallace and Marie-Ann Ewart and Docherty, {Craig K.} and Morrell, {Nicholas W.} and MacLean, {Margaret R.}",
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Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells. / Mair, Kirsty M.; Yang, Xu Dong; Long, Lu; White, Kevin; Wallace, Emma; Ewart, Marie-Ann; Docherty, Craig K.; Morrell, Nicholas W.; MacLean, Margaret R.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 191, No. 6, 15.03.2015, p. 693-703.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells

AU - Mair, Kirsty M.

AU - Yang, Xu Dong

AU - Long, Lu

AU - White, Kevin

AU - Wallace, Emma

AU - Ewart, Marie-Ann

AU - Docherty, Craig K.

AU - Morrell, Nicholas W.

AU - MacLean, Margaret R.

PY - 2015/3/15

Y1 - 2015/3/15

N2 - Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH). Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs). Methods: We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1. Measurements and Main Results: Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phospho-Smad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1+/-mice developed pulmonary hypertension (reversed by ovariectomy). Conclusions: We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.

AB - Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH). Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs). Methods: We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1. Measurements and Main Results: Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phospho-Smad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1+/-mice developed pulmonary hypertension (reversed by ovariectomy). Conclusions: We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.

KW - bone morphogenic protein type II

KW - estrogen

KW - proliferation

KW - pulmonary hypertension

KW - sex

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