Versican accumulates in vascular lesions in pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a lethal condition for which there is no effective curative pharmacotherapy. PAH is characterized by vasoconstriction, wall thickening of pulmonary arteries, and increased vascular resistance. Versican is a chondroitin sulfate proteoglycan in the vascular extracellular matrix that accumulates following vascular injury and promotes smooth-muscle cell proliferation in systemic arteries. Here, we investigated whether versican may play a similar role in PAH. Paraffin-embedded lung sections from patients who underwent lung transplantation to treat PAH were used for immunohistochemistry. The etiologies of PAH in the subjects involved in this study were idiopathic PAH, scleroderma, and congenital heart disease (atrial septal defect) with left-to-right shunt. Independent of the underlying etiology, increased versican immunostaining was observed in areas of medial thickening, in neointima, and in plexiform lesions. Western blot of lung tissue lysates confirmed accumulation of versican in patients with PAH. Double staining for versican and CD45 showed only occasional colocalization in neointima of high-grade lesions and plexiform lesions. In vitro, metabolic labeling with [(35)S]sulfate showed that human pulmonary artery smooth-muscle cells (hPASMCs) produce mainly chondroitin sulfate glycosaminoglycans. In addition, hypoxia, but not cyclic stretch, was demonstrated to increase both versican messenger RNA expression and protein synthesis by hPASMCs. Versican accumulates in vascular lesions of PAH, and the amount of versican correlates more with lesion severity than with underlying etiology or inflammation. Hypoxia is a possible regulator of versican accumulation, which may promote proliferation of pulmonary smooth-muscle cells and vascular remodeling in PAH.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Ya-Ting
YT
Chang
Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Christina K
CK
Chan
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Inger
I
Eriksson
Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Pamela Y
PY
Johnson
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Xiaofang
X
Cao
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Christian
C
Westöö
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Christian
C
Norvik
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Annika
A
Andersson-Sjöland
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Gunilla
G
Westergren-Thorsson
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Staffan
S
Johansson
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Ulf
U
Hedin
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Lena
L
Kjellén
Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Thomas N
TN
Wight
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Experimental Medical Science, Lund University, Lund, Sweden.
Karin
K
Tran-Lundmark
hypoxia; mechanical strain; pulmonary arterial hypertension; vascular smooth-muscle cell; versican
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