Your browser doesn't support javascript.
loading
GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension.
Chu, Xuran; Kheirollahi, Vahid; Lingampally, Arun; Chelladurai, Prakash; Valasarajan, Chanil; Vazquez-Armendariz, Ana Ivonne; Hadzic, Stefan; Khadim, Ali; Pak, Oleg; Rivetti, Stefano; Wilhelm, Jochen; Bartkuhn, Marek; Crnkovic, Slaven; Moiseenko, Alena; Heiner, Monika; Kraut, Simone; Atefi, Leila Sotoodeh; Koepke, Janine; Valente, Guilherme; Ruppert, Clemens; Braun, Thomas; Samakovlis, Christos; Alexopoulos, Ioannis; Looso, Mario; Chao, Cho-Ming; Herold, Susanne; Seeger, Werner; Kwapiszewska, Grazyna; Huang, Xiaoying; Zhang, Jin-San; Pullamsetti, Soni Savai; Weissmann, Norbert; Li, Xiaokun; El Agha, Elie; Bellusci, Saverio.
Affiliation
  • Chu X; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) (X.C., S.B.), Wenzhou Medical University, China.
  • Kheirollahi V; School of Pharmaceutical Sciences (X.C., X.L.), Wenzhou Medical University, China.
  • Lingampally A; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Chelladurai P; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Valasarajan C; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Vazquez-Armendariz AI; Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany.
  • Hadzic S; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Khadim A; Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.).
  • Pak O; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Rivetti S; Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.).
  • Wilhelm J; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Bartkuhn M; Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany.
  • Crnkovic S; Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.).
  • Moiseenko A; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Heiner M; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Kraut S; Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany.
  • Atefi LS; Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.).
  • Koepke J; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Valente G; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Ruppert C; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Braun T; Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.).
  • Samakovlis C; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Alexopoulos I; Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.).
  • Looso M; Ludwig Boltzmann Institute for Lung Vascular Research, Medical University Graz, Austria (S.C., G.K.).
  • Chao CM; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Herold S; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Seeger W; Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany.
  • Kwapiszewska G; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Zhang JS; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • Pullamsetti SS; Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.).
  • Weissmann N; Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.).
  • Li X; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
  • El Agha E; Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.).
  • Bellusci S; Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research
Circ Res ; 134(11): e133-e149, 2024 May 24.
Article in En | MEDLINE | ID: mdl-38639105
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.
Subject(s)
Key words
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vascular Remodeling / Zinc Finger Protein GLI1 / Hypertension, Pulmonary Limits: Animals / Humans / Male Language: En Journal: Circ Res Year: 2024 Type: Article Affiliation country: China
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vascular Remodeling / Zinc Finger Protein GLI1 / Hypertension, Pulmonary Limits: Animals / Humans / Male Language: En Journal: Circ Res Year: 2024 Type: Article Affiliation country: China