C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension
Abstract Metabolic reprogramming of vascular cells plays a crucial role in Pulmonary Arterial Hypertension (PAH), marked by a shift from oxidative phosphorylation to glycolysis (Warburg effect), altered purine biosynthesis, impaired glutaminolysis and fatty acid oxidation, driving endothelial and sm...
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Nature Portfolio
2025-08-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08661-0 |
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| author | Minhee Noh Ankita Mitra Lisa Krebes Werner Schmitz Jan Dudek Stuti Agarwal Christoph Maack Paula Arias-Loza Takahiro Higuchi Ivan Aleksic Vinicio A. de Jesus Perez Michaela Kuhn Swati Dabral |
| author_facet | Minhee Noh Ankita Mitra Lisa Krebes Werner Schmitz Jan Dudek Stuti Agarwal Christoph Maack Paula Arias-Loza Takahiro Higuchi Ivan Aleksic Vinicio A. de Jesus Perez Michaela Kuhn Swati Dabral |
| author_sort | Minhee Noh |
| collection | DOAJ |
| description | Abstract Metabolic reprogramming of vascular cells plays a crucial role in Pulmonary Arterial Hypertension (PAH), marked by a shift from oxidative phosphorylation to glycolysis (Warburg effect), altered purine biosynthesis, impaired glutaminolysis and fatty acid oxidation, driving endothelial and smooth muscle cell hyperproliferation. The metabolic alterations underlying pericyte dysfunction in PAH remain largely unexplored. Here, we investigated the metabolic alterations in PAH lung pericytes and the impact of C-type natriuretic peptide (CNP) and Guanylyl Cyclase-B/cyclic GMP signaling on these changes. Our results demonstrate that PAH pericytes exhibit increased glucose uptake, glycolysis, and de novo pyrimidine synthesis, promoting their hyperproliferation. These changes are driven by the upregulated glucose transporter, GLUT-1 and Pyruvate dehydrogenase kinase 1, along with enhanced CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) activity, both in vitro and in situ. CNP counteracts these alterations through activation of cGMP-dependent kinase I, reducing HIF-1α and GLUT-1 expression and thereby glucose uptake. Additionally, CNP activates Phosphodiesterase 2 A and thereby inhibits CAD activation and de novo pyrimidine synthesis. Accordingly, CNP prevented growth factor-induced proliferation and metabolic changes in murine pericytes within precision-cut lung slices. This study highlights dysregulated metabolic pathways in PAH pericytes and the therapeutic potential of CNP. |
| format | Article |
| id | doaj-art-79831f77c38d4b1eb248bb5efaa9d53d |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-79831f77c38d4b1eb248bb5efaa9d53d2025-08-20T03:05:56ZengNature PortfolioCommunications Biology2399-36422025-08-018111610.1038/s42003-025-08661-0C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertensionMinhee Noh0Ankita Mitra1Lisa Krebes2Werner Schmitz3Jan Dudek4Stuti Agarwal5Christoph Maack6Paula Arias-Loza7Takahiro Higuchi8Ivan Aleksic9Vinicio A. de Jesus Perez10Michaela Kuhn11Swati Dabral12Institute of Physiology, University of WürzburgDivisions of Pulmonary and Critical Care Medicine and Stanford Cardiovascular Institute, Stanford UniversityInstitute of Physiology, University of WürzburgInstitute of Biochemistry and Molecular Biology, University of WürzburgComprehensive Heart Failure Center, University Hospital WürzburgDivisions of Pulmonary and Critical Care Medicine and Stanford Cardiovascular Institute, Stanford UniversityComprehensive Heart Failure Center, University Hospital WürzburgDepartment of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital WürzburgDepartment of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital WürzburgDepartment of Thoracic and Cardiovascular Surgery, University Hospital WürzburgDivisions of Pulmonary and Critical Care Medicine and Stanford Cardiovascular Institute, Stanford UniversityInstitute of Physiology, University of WürzburgInstitute of Physiology, University of WürzburgAbstract Metabolic reprogramming of vascular cells plays a crucial role in Pulmonary Arterial Hypertension (PAH), marked by a shift from oxidative phosphorylation to glycolysis (Warburg effect), altered purine biosynthesis, impaired glutaminolysis and fatty acid oxidation, driving endothelial and smooth muscle cell hyperproliferation. The metabolic alterations underlying pericyte dysfunction in PAH remain largely unexplored. Here, we investigated the metabolic alterations in PAH lung pericytes and the impact of C-type natriuretic peptide (CNP) and Guanylyl Cyclase-B/cyclic GMP signaling on these changes. Our results demonstrate that PAH pericytes exhibit increased glucose uptake, glycolysis, and de novo pyrimidine synthesis, promoting their hyperproliferation. These changes are driven by the upregulated glucose transporter, GLUT-1 and Pyruvate dehydrogenase kinase 1, along with enhanced CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) activity, both in vitro and in situ. CNP counteracts these alterations through activation of cGMP-dependent kinase I, reducing HIF-1α and GLUT-1 expression and thereby glucose uptake. Additionally, CNP activates Phosphodiesterase 2 A and thereby inhibits CAD activation and de novo pyrimidine synthesis. Accordingly, CNP prevented growth factor-induced proliferation and metabolic changes in murine pericytes within precision-cut lung slices. This study highlights dysregulated metabolic pathways in PAH pericytes and the therapeutic potential of CNP.https://doi.org/10.1038/s42003-025-08661-0 |
| spellingShingle | Minhee Noh Ankita Mitra Lisa Krebes Werner Schmitz Jan Dudek Stuti Agarwal Christoph Maack Paula Arias-Loza Takahiro Higuchi Ivan Aleksic Vinicio A. de Jesus Perez Michaela Kuhn Swati Dabral C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension Communications Biology |
| title | C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension |
| title_full | C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension |
| title_fullStr | C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension |
| title_full_unstemmed | C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension |
| title_short | C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension |
| title_sort | c type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension |
| url | https://doi.org/10.1038/s42003-025-08661-0 |
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