Abstract
Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit+ cells and severe pulmonary arterial hypertension. We detected c-kit+ cells expressing endothelial (von Willebrand Factor) or smooth muscle cell/myofibroblast (α-smooth muscle actin) markers in pulmonary arterial lesions of SU5416/chronic hypoxia rats. We found increased expression of CXC chemokine ligand 12 in the lung tissue of SU5416/chronic hypoxia rats. In our prevention study, AMD3100, an inhibitor of the CXC chemokine ligand 12 receptor, CXC chemokine receptor 4, only moderately decreased pulmonary arterial obliteration and pulmonary hypertension in SU5416/chronic hypoxia animals. AMD3100 treatment reduced the number of proliferating c-kit+ α-smooth muscle actin+ cells and pulmonary arterial muscularization and did not affect c-kit+ von Willebrand Factor+ cell numbers. Both c-kit+ cell types expressed CXC chemokine receptor 4. In conclusion, our data demonstrate that in the SU5416/chronic hypoxia model of severe pulmonary hypertension, the CXC chemokine receptor 4-expressing c-kit+ α-smooth muscle actin+ cells contribute to pulmonary arterial muscularization. In contrast, vascular lumen obliteration by c-kit+ von Willebrand Factor+ cells is largely independent of CXC chemokine receptor 4.
Highlights
Severe pulmonary arterial hypertension (PAH) is characterized by a lumen-obliterating pulmonary microvasculopathy and complex, multicellular plexiform lesions [1]
We investigated the development of vascular obliteration in an animal model of severe PAH that predictably generates obliterative pulmonary arterial lesions resembling those observed in the lungs of patients with severe PAH [4,24]
A variety of stem and progenitor cell markers has been detected in vascular lesions of patients with severe PAH [16,17,26]
Summary
Severe pulmonary arterial hypertension (PAH) is characterized by a lumen-obliterating pulmonary microvasculopathy and complex, multicellular plexiform lesions [1]. These vascular lesions and abnormal vessel tone lead to increased pulmonary vascular resistance and right heart failure [2]. Additional factors that are likely pathobiologically relevant, are mutations in the bone morphogenic protein receptor 2 and inflammation [5]._ENREF_6 the nature and the origin of the phenotypically altered and proliferating cells that occlude the pulmonary vascular lumen are incompletely understood. One way to identify progenitor cells in addition to their proliferative capacity is the use of cellular markers that are not expressed by terminally differentiated cells, such as c-kit, a tyrosine kinase receptor for stem cell factor. C-kit+ stem cells can repopulate airways and vessels [12] and a recent study has identified that mouse lung ECs contain a c-kit+ population of rare vascular endothelial stem cells that can generate functional blood vessels [13]
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