Journalartikel

Jahr der Veröffentlichung: 2024

Seiten: e133-e149

Zeitschrift: Circulation Research

Bandnummer: 134

Heftnummer: 11

ISSN: 0009-7330

eISSN: 1524-4571

DOI Link: https://doi.org/10.1161/CIRCRESAHA.123.323736

Verlag: American Heart Association

Abstract: 

Background:The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs).
Methods:Gli1Cre-ERT2; tdTomatoflox mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature.RESULTS:The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an Acta2high fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation.
Conclusions:Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.

Harvard-Zitierstil: Chu, X., Kheirollahi, V., Lingampally, A., Chelladurai, P., Valasarajan, C., Vazquez-Armendariz, A., et al. (2024) GLI1+Cells Contribute to Vascular Remodeling in Pulmonary Hypertension, Circulation Research, 134(11), pp. e133-e149. https://doi.org/10.1161/CIRCRESAHA.123.323736

APA-Zitierstil: Chu, X., Kheirollahi, V., Lingampally, A., Chelladurai, P., Valasarajan, C., Vazquez-Armendariz, A., Hadzic, S., Khadim, A., Pak, O., Rivetti, S., Wilhelm, J., Bartkuhn, M., Crnkovic, S., Moiseenko, A., Heiner, M., Kraut, S., Atefi, L., Koepke, J., Valente, G., ...Bellusci, S. (2024). GLI1+Cells Contribute to Vascular Remodeling in Pulmonary Hypertension. Circulation Research. 134(11), e133-e149. https://doi.org/10.1161/CIRCRESAHA.123.323736