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"Faces" of the day:

Katharina Jandl

Nina Höller

Nariae Baik-Schneditz

Ellen Heitzer

Marianne Brodmann

Ewald Kolesnik

Bernhard Schwaberger

Maximilian Seles

Gabor Toth-Gayor

Lukas Peter Mileder

Niels Hammer

Christian Josef Hill

Christian Viertler

Philipp Klaritsch

Daniel Scherr

Harald Köfeler

Gerhard Pichler

Roland Malli

Michael Fuchsjäger

Gernot Plank

Peter Fickert

Richard Zigeuner

Peter Holzer

Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Chu, X; Kheirollahi, V; Lingampally, A; Chelladurai, P; Valasarajan, C; Vazquez-Armendariz, AI; Hadzic, S; Khadim, A; Pak, O; Rivetti, S; Wilhelm, J; Bartkuhn, M; Crnkovic, S; Moiseenko, A; Heiner, M; Kraut, S; Sotoodeh, L; Koepke, J; Valente, G; Ruppert, C; Braun, T; Samakovlis, C; Alexopoulos, I; Looso, M; Chao, CM; Herold, S; Seeger, W; Kwapiszewska, G; Huang, X; Zhang, JS; Pullamsetti, SS; Weissmann, N; Li, X; El, Agha, E; Bellusci, S.
GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension.
Circ Res. 2024; Doi: 10.1161/CIRCRESAHA.123.323736
Web of Science PubMed FullText FullText_MUG

 

Co-authors Med Uni Graz

Crnkovic Slaven

Kwapiszewska-Marsh Grazyna

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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: Gli1^Cre-ERT2; tdTomato^flox 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 Acta2^high fraction of cells with pathways in cancer and MAPK 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.

Find related publications in this database (Keywords)

actins

blood pressure

hypertension, pulmonary

hypoxia

vascular remodeling

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