Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-β in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension

Nancy F. Tojais, Aiqin Cao, Ying Ju Lai, Lingli Wang, Pin I. Chen, Miguel A.Alejandre Alcazar, Vinicio A. De Jesus Perez, Rachel K. Hopper, Christopher J. Rhodes, Matthew A. Bill, Lynn Sakai, Marlene Rabinovitch

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objective - We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly. Approach and Results - Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFβ1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension. Conclusions - Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

Original languageEnglish (US)
Pages (from-to)1559-1569
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein 2
Elastic Tissue
Transforming Growth Factors
Pulmonary Hypertension
Elastin
Adventitia
Lung
Fibroblast Growth Factor 1
Bone Morphogenetic Proteins
Hypertension
Smooth Muscle Myocytes
Fibroblasts
Messenger RNA
Proteins
Codependency (Psychology)
Pancreatic Elastase
Heterozygote
Fibrillin-1
Mutation

Keywords

  • BMPR2 receptor
  • elastin
  • fibrillin-1
  • fibroblasts
  • hypertension, pulmonary
  • smooth muscle cells
  • TGF-beta-1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-β in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. / Tojais, Nancy F.; Cao, Aiqin; Lai, Ying Ju; Wang, Lingli; Chen, Pin I.; Alcazar, Miguel A.Alejandre; De Jesus Perez, Vinicio A.; Hopper, Rachel K.; Rhodes, Christopher J.; Bill, Matthew A.; Sakai, Lynn; Rabinovitch, Marlene.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 37, No. 8, 01.08.2017, p. 1559-1569.

Research output: Contribution to journalArticle

Tojais, Nancy F. ; Cao, Aiqin ; Lai, Ying Ju ; Wang, Lingli ; Chen, Pin I. ; Alcazar, Miguel A.Alejandre ; De Jesus Perez, Vinicio A. ; Hopper, Rachel K. ; Rhodes, Christopher J. ; Bill, Matthew A. ; Sakai, Lynn ; Rabinovitch, Marlene. / Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-β in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. In: Arteriosclerosis, thrombosis, and vascular biology. 2017 ; Vol. 37, No. 8. pp. 1559-1569.
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abstract = "Objective - We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly. Approach and Results - Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFβ1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension. Conclusions - Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.",
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T1 - Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-β in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension

AU - Tojais, Nancy F.

AU - Cao, Aiqin

AU - Lai, Ying Ju

AU - Wang, Lingli

AU - Chen, Pin I.

AU - Alcazar, Miguel A.Alejandre

AU - De Jesus Perez, Vinicio A.

AU - Hopper, Rachel K.

AU - Rhodes, Christopher J.

AU - Bill, Matthew A.

AU - Sakai, Lynn

AU - Rabinovitch, Marlene

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N2 - Objective - We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly. Approach and Results - Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFβ1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension. Conclusions - Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

AB - Objective - We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly. Approach and Results - Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFβ1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension. Conclusions - Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

KW - BMPR2 receptor

KW - elastin

KW - fibrillin-1

KW - fibroblasts

KW - hypertension, pulmonary

KW - smooth muscle cells

KW - TGF-beta-1

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