Inhaltspezifische Aktionen


Origin and fate of vascular myofibroblasts and smooth muscle cells during pulmonary vascular remodeling and reverse remodeling

Pulmonary vascular remodeling is a feature of pulmonary hypertension (PH), a disease in which the blood pressure inside the pulmonary circulation is abnormally elevated. The latter is a result of both increased muscularization of already muscularized vessels and de novo muscularization of normally non-muscularized (distal) vessels. Such remodeling process increases pulmonary vascular resistance and stiffness, and if left untreated, can lead to right heart failure due to prolonged burden on the right ventricle. Pulmonary hypertension is largely present in patients suffering from chronic lung diseases such as COPD (Group 3 PH).

The origin of vascular smooth muscle cells (VSMCs) that emerge during PH development has been intensely investigated. The rationale for that is that identifying such cell-of-origin might help develop targeted therapy for future patients. Although it has been widely believed that PH-associated vascular smooth muscle cells (VSMCs) arise predominantly due to the expansion of pre-existing VSMCs located in the proximal part of pulmonary vessels (1), we recently demonstrated using two independent models of PH in mice, hypoxia and cigarette-smoke exposure, that there is a major additional source of VSMCs during PH pathogenesis represented by mesenchymal cells expressing the sonic hedgehog target gene glioma-associated oncogene 1 (Gil1) (2) (Fig. 1). Selective genetic ablation of these cells attenuates PH development in mice, and we show evidence that our findings are translatable to both human idiopathic pulmonary arterial hypertension (IPAH; Group 1) and Group 3 PH. Our study therefore opens a new avenue for testing novel therapeutic interventions in PH.

In the next funding period, we aim to characterize, genetically manipulate, and ablate the specific subset of GLI1+ cells contributing to PH, with special emphasis on FGF signaling in the context of both mouse and human-derived lung material.



  1. X. Chu, N. Ahmadvand, J.-S. Zhang, W. Seeger, S. Bellusci, E. El Agha, Evidence for Multiple Origins of De Novo Formed Vascular Smooth Muscle Cells in Pulmonary Hypertension: Challenging the Dominant Model of Pre-Existing Smooth Muscle Expansion. Int. J. Environ. Res. Public. Health 18, 8584 (2021).
  2. X. Chu, V. Kheirollahi, A. Lingampally, P. Chelladurai, C. Valasarajan, A. I. Vazquez-Armendariz, S. Hadzic, A. Khadim, O. Pak, S. Rivetti, J. Wilhelm, M. Bartkuhn, S. Crnkovic, A. Moiseenko, M. Heiner, S. Kraut, L. S. Atefi, J. Koepke, G. Valente, C. Ruppert, T. Braun, C. Samakovlis, I. Alexopoulos, M. Looso, C.-M. Chao, S. Herold, W. Seeger, G. Kwapiszewska, X. Huang, J.-S. Zhang, S. S. Pullamsetti, N. Weissmann, X. Li, E. El Agha, S. Bellusci, GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension. Circ. Res. 134, e133–e149 (2024).