CXCR4 inhibition ameliorates severe obliterative pulmonary hypertension and accumulation of C-kit⁺ cells in rats.
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| 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.
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| Authors | Daniela Farkas, Donatas Kraskauskas, Jennifer I Drake, Aysar A Alhussaini, Vita Kraskauskiene, Harm J Bogaard, Carlyne D Cool, Norbert F Voelkel, Laszlo Farkas |
| Journal | PloS one (PLoS One) Vol. 9 Issue 2 Pg. e89810 ( 2014) ISSN: 1932-6203 [Electronic] United States |
| PMID | 24587052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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