Resident PW1(+) Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension
Résumé
Rationale: Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1+ progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro.
Objective: To determine the role of pulmonary PW1+ progenitor cells in vascular remodeling characteristic of pulmonary arterial hypertension.
Methods and Results: We investigated their contribution during chronic hypoxia–induced vascular remodeling in Pw1nLacZ+/− mouse expressing β-galactosidase in PW1+ cells and in differentiated cells derived from PW1+ cells. PW1+ progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, 3 distinct myogenic PW1+ cell populations were isolated from the mouse lung of which 2 were significantly increased after 4 days of chronic hypoxia. The number of proliferating pulmonary PW1+ cells and the proportion of β-gal+ vascular SMC were increased, indicating a recruitment of PW1+ cells and their differentiation into vascular SMC during early chronic hypoxia–induced neomuscularization. CXCR4 inhibition using AMD3100 prevented PW1+ cells differentiation into SMC but did not inhibit their proliferation. Bone marrow transplantation experiments showed that the newly formed β-gal+ SMC were not derived from circulating bone marrow–derived PW1+ progenitor cells, confirming a resident origin of the recruited PW1+ cells. The number of pulmonary PW1+ cells was also increased in rats after monocrotaline injection. In lung from pulmonary arterial hypertension patients, PW1-expressing cells were observed in large numbers in remodeled vascular structures.
Conclusions: These results demonstrate the existence of a novel population of resident SMC progenitor cells expressing PW1 and participating in pulmonary hypertension–associated vascular remodeling.
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