Pulmonary vascular fibrosis in pulmonary hypertension – The role of the extracellular matrix as a therapeutic target

Jandl, Katharina; Radic, Nemanja; Zeder, Katarina; Kovacs, Gabor; Kwapiszewska, Grazyna

doi:10.1016/j.pharmthera.2023.108438

Cited by 14 publications

(3 citation statements)

References 173 publications

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“…The SAMP8 TAC mice had focal regions of pulmonary fibrosis surrounding arteries and airways, which is a characteristic of PH tissue remodeling. 56 , 57 , 58 Of note, we previously reported that a profibrogenic crosslinking enzyme, tissue transglutaminase, was elevated in a pressure‐overloaded TAC 41 and a senescent‐prone mouse model of aging 49 where myocardial fibrosis and heart failure with preserved ejection fraction have been described. We also identified that elevation of transglutaminase activity is causative for fibrogenic remodeling, including collagen deposition in experimental mouse models of cardiopulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Positron Emission Tomography and Molecular Magnetic Resonance Imaging of Cardiopulmonary Fibrosis in a Mouse Model of Left Ventricular Dysfunction

Moon,

Zhou,

Ning

et al. 2024

JAHA

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Background Aging‐associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)–magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. Methods and Results Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6‐month‐old senescence‐accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET‐MRI at 4.7 T. Collagen‐targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium‐ or lung‐to‐muscle ratio. Percent signal intensity increase and Δ lung‐to‐muscle ratio were computed from the pre‐/postinjection magnetic resonance images. Elevated allysine in the heart ( P =0.02) and lungs ( P =0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase ( P <0.0001) and Δlung‐to‐muscle ratio ( P <0.0001). Hydroxyproline in the heart ( P <0.0001) and lungs ( P <0.01) were elevated in TAC mice, which corresponded to an increase in heart (myocardium‐to‐muscle ratio, P =0.02) and lung (lung‐to‐muscle ratio, P <0.001) PET measurements. Pressure‐volume loop and echocardiography demonstrated adverse left ventricular remodeling, function, and increased right ventricular systolic pressure in TAC mice. Conclusions Administration of collagen‐targeted PET and allysine‐targeted MR probes led to elevated PET–magnetic resonance imaging signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET–magnetic resonance imaging protocol.

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Section: Discussionmentioning

confidence: 99%

Simultaneous Positron Emission Tomography and Molecular Magnetic Resonance Imaging of Cardiopulmonary Fibrosis in a Mouse Model of Left Ventricular Dysfunction

Moon,

Zhou,

Ning

et al. 2024

JAHA

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“…The SAMP8 TAC mice had focal regions of pulmonary fibrosis surrounding arteries and airways, which is a characteristic of PH tissue remodeling. [56][57][58] Of note, we previously reported that a pro-fibrogenic crosslinking enzyme, tissue transglutaminase (TG2), was elevated in a pressure-overloaded TAC 41 and a senescent-prone mouse model of aging 49 where myocardial fibrosis and HFpEF have been described. We also identified that elevation of TG2 activity is causative for fibrogenic remodeling including collagen deposition in experimental mouse models of cardiopulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction

Moon,

Zhou,

Ning

et al. 2023

Preprint

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BackgroundAging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in an LV dysfunction model.MethodsLV dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone (SAMP8) mice, a subset of mice received sham surgery. Three weeks post-surgery, mice underwent simultaneous PET-MR imaging at 4.7 T. Collagen–targeted PET and fibrogenesis MR probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent signal increase (%SI) and ΔLMR were computed from the pre-/post-injection MR images. Tissue specimens were analyzed for hydroxyproline (Hyp) and allysine content. Ventricular structure and function were measured by echocardiography and hemodynamic pressure-volume (PV) loop analysis.ResultsAllysine in the heart (22±5 (TAC), 13±5 (sham) nmol/g,P=0.02) and lungs (7.5±4 (TAC), 5.8±2 (sham) nmol/lung,P=0.17) of TAC mice corresponded to an increase in myocardial MRI %SI (29±15 (TAC), 6.1±4 (sham),P<0.0001) and ΔLMR (0.3±0.1 (TAC), 0.08±0.1 (sham),P<0.0001). Hyp in the heart (555±90 (TAC), 400±80 (sham) µg/g,P<0.0001) and lungs (189±63 (TAC), 143±31 (sham) µg/lung,P<0.01) were elevated in TAC mice, which corresponded to an increase in PET signal (MMR: 1.8±0.1 (TAC), 1.6±0.2 (sham),P=0.02; LMR: 1.5±0.1 (TAC), 1.2±0.1 (sham),P<0.001). PV loop and echocardiography demonstrated adverse LV remodeling, function, and increased right ventricular systolic pressure in TAC mice.ConclusionsAdministration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-MRI signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-MR imaging protocol.

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“…In summary, PAAFs, as both contributors and responders to microenvironmental stiffness, are a critical contributor to the profibrotic phenotype of the PH vessel wall. Future studies will need to consider age and sex differences in the exploration of numerous potential anti- or reverse-ECM remodeling therapies [ 82 ].…”

Section: Fibroblasts’ Contribution To Pulmonary Vascular Remodeling I...mentioning

confidence: 99%

Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

Zhang,

Li,

et al. 2024

Cells

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Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.

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Pulmonary vascular fibrosis in pulmonary hypertension – The role of the extracellular matrix as a therapeutic target

Cited by 14 publications

References 173 publications

Simultaneous Positron Emission Tomography and Molecular Magnetic Resonance Imaging of Cardiopulmonary Fibrosis in a Mouse Model of Left Ventricular Dysfunction

Simultaneous Positron Emission Tomography and Molecular Magnetic Resonance Imaging of Cardiopulmonary Fibrosis in a Mouse Model of Left Ventricular Dysfunction

Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction

Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

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