CCN1 suppresses pulmonary vascular smooth muscle contraction in response to hypoxia

Seon Jin Lee, Meng Zhang, Kebin Hu, Ling Lin, Duo Zhang, Yang Jin

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Pulmonary vasoconstriction and increased vascular resistance are common features in pulmonary hypertension (PH). One of the contributing factors in the development of pulmonary vasoconstriction is increased pulmonary artery smooth muscle cell (PASMC) contraction. Here we report that CCN1, an extracellular matrix molecule, suppressed PASMC contraction in response to hypoxia. CCN1 (Cyr61), discovered in past decade, belongs to the Cyr61-CTGF-Nov (CCN) family. It carries a variety of cellular functions, including angiogenesis and cell adhesion, death, and proliferation. Hypoxia robustly upregulated the expression of CCN1 in the pulmonary vessels and lung parenchyma. Given that CCN1 is a secreted protein and functions in a paracine manner, we examined the potential effects of CCN1 on the adjacent smooth muscle cells. Interestingly, bioactive recombinant CCN1 significantly suppressed hypoxia-induced contraction in human PASMCs in vitro. Consistently, in the in vivo functional studies, administration of bioactive CCN1 protein significantly decreased right ventricular pressure in three different PH animal models. Mechanistically, protein kinase A–pathway inhibitors abolished the effects of CCN1 in suppressing PASMC contraction. Furthermore, CCN1-inhibited smooth muscle contraction was independent of the known vasodilators, such as nitric oxide. Taken together, our studies indicated a novel cellular function of CCN1, potentially regulating the pathogenesis of PH.

Original languageEnglish (US)
Pages (from-to)716-722
Number of pages7
JournalPulmonary Circulation
Volume5
Issue number4
DOIs
StatePublished - Oct 7 2015

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Muscle Contraction
Vascular Smooth Muscle
Smooth Muscle Myocytes
Pulmonary Hypertension
Pulmonary Artery
Lung
Vasoconstriction
Cysteine-Rich Protein 61
Ventricular Pressure
Protein Kinase Inhibitors
Vasodilator Agents
Cell Adhesion
Vascular Resistance
Extracellular Matrix
Smooth Muscle
Nitric Oxide
Cell Death
Animal Models
Cell Proliferation
Hypoxia

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine

Cite this

Lee, Seon Jin ; Zhang, Meng ; Hu, Kebin ; Lin, Ling ; Zhang, Duo ; Jin, Yang. / CCN1 suppresses pulmonary vascular smooth muscle contraction in response to hypoxia. In: Pulmonary Circulation. 2015 ; Vol. 5, No. 4. pp. 716-722.
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abstract = "Pulmonary vasoconstriction and increased vascular resistance are common features in pulmonary hypertension (PH). One of the contributing factors in the development of pulmonary vasoconstriction is increased pulmonary artery smooth muscle cell (PASMC) contraction. Here we report that CCN1, an extracellular matrix molecule, suppressed PASMC contraction in response to hypoxia. CCN1 (Cyr61), discovered in past decade, belongs to the Cyr61-CTGF-Nov (CCN) family. It carries a variety of cellular functions, including angiogenesis and cell adhesion, death, and proliferation. Hypoxia robustly upregulated the expression of CCN1 in the pulmonary vessels and lung parenchyma. Given that CCN1 is a secreted protein and functions in a paracine manner, we examined the potential effects of CCN1 on the adjacent smooth muscle cells. Interestingly, bioactive recombinant CCN1 significantly suppressed hypoxia-induced contraction in human PASMCs in vitro. Consistently, in the in vivo functional studies, administration of bioactive CCN1 protein significantly decreased right ventricular pressure in three different PH animal models. Mechanistically, protein kinase A–pathway inhibitors abolished the effects of CCN1 in suppressing PASMC contraction. Furthermore, CCN1-inhibited smooth muscle contraction was independent of the known vasodilators, such as nitric oxide. Taken together, our studies indicated a novel cellular function of CCN1, potentially regulating the pathogenesis of PH.",
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CCN1 suppresses pulmonary vascular smooth muscle contraction in response to hypoxia. / Lee, Seon Jin; Zhang, Meng; Hu, Kebin; Lin, Ling; Zhang, Duo; Jin, Yang.

In: Pulmonary Circulation, Vol. 5, No. 4, 07.10.2015, p. 716-722.

Research output: Contribution to journalArticle

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