Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension

Cheol Hwangbo, Heon Woo Lee, Hyeseon Kang, Hyekyung Ju, David S. Wiley, Irinna Papangeli, Jinah Han, Jun Dae Kim, William P. Dunworth, Xiaoyue Hu, Seyoung Lee, Omar El-Hely, Avraham Sofer, Boryeong Pak, Laura Peterson, Suzy Comhair, Eun Mi Hwang, Jae-Yong Park, Jean Leon Thomas, Victoria L. Bautch & 3 others Serpil C. Erzurum, Hyung J. Chun, Suk Won Jin

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Bone morphogenetic protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP receptor type 2 (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. Methods: We used a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between vascular endothelial growth factor receptor 3 (VEGFR3) and BMPR2. Additional in vitro studies were performed by using human endothelial cells, including primary lung endothelial cells from subjects with PAH. Results: Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial-specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension. Consistent with these data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from human PAH subjects, and reconstitution of VEGFR3 expression in PAH pulmonary arterial endothelial cells restored BMP signaling responses. Conclusions: Our findings identify VEGFR3 as a key regulator of endothelial BMPR2 signaling and a potential determinant of PAH penetrance in humans.

Original languageEnglish
Pages (from-to)2288-2298
Number of pages11
JournalCirculation
Volume135
Issue number23
DOIs
Publication statusPublished - 2017 Jun 6

Fingerprint

Type II Bone Morphogenetic Protein Receptors
Vascular Endothelial Growth Factor Receptor-3
Pulmonary Hypertension
Bone Morphogenetic Proteins
Endothelial Cells
Zebrafish
Lung
Embryonic Structures
Mutation
Penetrance
Endocytosis
Blood Vessels
Phosphorylation
Ligands

Keywords

  • Bone morphogenetic protein receptors, type II
  • Endothelial cells
  • FLT4 protein, human
  • Hypertension, pulmonary

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension. / Hwangbo, Cheol; Lee, Heon Woo; Kang, Hyeseon; Ju, Hyekyung; Wiley, David S.; Papangeli, Irinna; Han, Jinah; Kim, Jun Dae; Dunworth, William P.; Hu, Xiaoyue; Lee, Seyoung; El-Hely, Omar; Sofer, Avraham; Pak, Boryeong; Peterson, Laura; Comhair, Suzy; Hwang, Eun Mi; Park, Jae-Yong; Thomas, Jean Leon; Bautch, Victoria L.; Erzurum, Serpil C.; Chun, Hyung J.; Jin, Suk Won.

In: Circulation, Vol. 135, No. 23, 06.06.2017, p. 2288-2298.

Research output: Contribution to journalArticle

Hwangbo, C, Lee, HW, Kang, H, Ju, H, Wiley, DS, Papangeli, I, Han, J, Kim, JD, Dunworth, WP, Hu, X, Lee, S, El-Hely, O, Sofer, A, Pak, B, Peterson, L, Comhair, S, Hwang, EM, Park, J-Y, Thomas, JL, Bautch, VL, Erzurum, SC, Chun, HJ & Jin, SW 2017, 'Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension', Circulation, vol. 135, no. 23, pp. 2288-2298. https://doi.org/10.1161/CIRCULATIONAHA.116.025390
Hwangbo, Cheol ; Lee, Heon Woo ; Kang, Hyeseon ; Ju, Hyekyung ; Wiley, David S. ; Papangeli, Irinna ; Han, Jinah ; Kim, Jun Dae ; Dunworth, William P. ; Hu, Xiaoyue ; Lee, Seyoung ; El-Hely, Omar ; Sofer, Avraham ; Pak, Boryeong ; Peterson, Laura ; Comhair, Suzy ; Hwang, Eun Mi ; Park, Jae-Yong ; Thomas, Jean Leon ; Bautch, Victoria L. ; Erzurum, Serpil C. ; Chun, Hyung J. ; Jin, Suk Won. / Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension. In: Circulation. 2017 ; Vol. 135, No. 23. pp. 2288-2298.
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abstract = "Background: Bone morphogenetic protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP receptor type 2 (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. Methods: We used a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between vascular endothelial growth factor receptor 3 (VEGFR3) and BMPR2. Additional in vitro studies were performed by using human endothelial cells, including primary lung endothelial cells from subjects with PAH. Results: Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial-specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension. Consistent with these data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from human PAH subjects, and reconstitution of VEGFR3 expression in PAH pulmonary arterial endothelial cells restored BMP signaling responses. Conclusions: Our findings identify VEGFR3 as a key regulator of endothelial BMPR2 signaling and a potential determinant of PAH penetrance in humans.",
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T1 - Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension

AU - Hwangbo, Cheol

AU - Lee, Heon Woo

AU - Kang, Hyeseon

AU - Ju, Hyekyung

AU - Wiley, David S.

AU - Papangeli, Irinna

AU - Han, Jinah

AU - Kim, Jun Dae

AU - Dunworth, William P.

AU - Hu, Xiaoyue

AU - Lee, Seyoung

AU - El-Hely, Omar

AU - Sofer, Avraham

AU - Pak, Boryeong

AU - Peterson, Laura

AU - Comhair, Suzy

AU - Hwang, Eun Mi

AU - Park, Jae-Yong

AU - Thomas, Jean Leon

AU - Bautch, Victoria L.

AU - Erzurum, Serpil C.

AU - Chun, Hyung J.

AU - Jin, Suk Won

PY - 2017/6/6

Y1 - 2017/6/6

N2 - Background: Bone morphogenetic protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP receptor type 2 (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. Methods: We used a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between vascular endothelial growth factor receptor 3 (VEGFR3) and BMPR2. Additional in vitro studies were performed by using human endothelial cells, including primary lung endothelial cells from subjects with PAH. Results: Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial-specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension. Consistent with these data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from human PAH subjects, and reconstitution of VEGFR3 expression in PAH pulmonary arterial endothelial cells restored BMP signaling responses. Conclusions: Our findings identify VEGFR3 as a key regulator of endothelial BMPR2 signaling and a potential determinant of PAH penetrance in humans.

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KW - Bone morphogenetic protein receptors, type II

KW - Endothelial cells

KW - FLT4 protein, human

KW - Hypertension, pulmonary

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