Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension.

Abstract

AIMS:

Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study, we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH.

METHODS AND RESULTS:

In normoxia, Hspg2(Δ3/Δ3) mice, deficient in perlecan HS, had reduced pericytes and muscularization of intra-acinar vessels. Pulmonary angiography revealed a peripheral perfusion defect. Despite these abnormalities, right ventricular systolic pressure (RVSP) and myocardial mass remained normal. After 4 weeks of hypoxia, increases in the proportion of muscularized vessels, RVSP, and right ventricular hypertrophy were significantly less in Hspg2(Δ3/Δ3) compared with wild type. The early phase of hypoxia induced a significantly lower increase in fibroblast growth factor receptor-1 (FGFR1) protein level and receptor phosphorylation, and reduced pulmonary artery smooth muscle cell (PASMC) proliferation in Hspg2(Δ3/Δ3). At 4 weeks, FGF2 mRNA and protein were also significantly reduced in Hspg2(Δ3/Δ3) lungs. Ligand and carbohydrate engagement assay showed that perlecan HS is required for HS-FGF2-FGFR1 ternary complex formation. In vitro, proliferation assays showed that PASMC proliferation is reduced by selective FGFR1 inhibition. PASMC adhesion to fibronectin was higher in Hspg2(Δ3/Δ3) compared with wild type.

CONCLUSIONS:

Perlecan HS chains are important for normal vascular arborization and recruitment of pericytes to pulmonary vessels. Perlecan HS deficiency also attenuates hypoxia-induced PH, where the underlying mechanisms involve impaired FGF2/FGFR1 interaction, inhibition of PASMC growth, and altered cell-matrix interactions.

• Authors: Ya-Ting Chang, Chi-Nan Tseng, Philip Tannenberg, Linnéa Eriksson, Ke Yuan, Vinicio A de Jesus Perez, Johan Lundberg, Mariette Lengquist, Ileana Ruxandra Botusan, Sergiu-Bogdan Catrina, Phan-Kiet Tran, Ulf Hedin, Karin Tran-Lundmark
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 107 Issue 1 Pg. 20-31 (Jul 01 2015) ISSN: 1755-3245 [Electronic] England
• PMID: 25952902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected].

Chemical References

• Heparan Sulfate Proteoglycans
• Fibroblast Growth Factor 2
• perlecan
• Fgfr1 protein, mouse
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Animals
• Cell Adhesion
• Cell Proliferation
• Cells, Cultured
• Female
• Fibroblast Growth Factor 2 (analysis)
• Heparan Sulfate Proteoglycans (analysis, deficiency, metabolism)
• Hypertension, Pulmonary (etiology, prevention & control)
• Hypoxia (complications)
• Mice
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (physiology)
• Phosphorylation
• Pulmonary Artery (diagnostic imaging, physiology)
• Radiography
• Receptor, Fibroblast Growth Factor, Type 1 (metabolism)