https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Jena Klinik für Innere Medizin I - Kardiologie Jena, Deutschland; 2Herz-Kreislauf-Zentrum, Klinikum Hersfeld-Rotenburg GmbH Klinik für Kardiologie, Angiologie und Intensivmedizin Rotenburg an der Fulda, Deutschland; 3Universitätsklinikum Jena Klinik für Herz- und Thoraxchirurgie Jena, Deutschland; 4Universitätsklinikum Jena Institut für Rechtsmedizin, Sektion Pathologie Jena, Deutschland; 5Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland
Background and Aims: Pulmonary hypertension (PH) remains an aetiologically and clinically heterogenous disorder that is predominately driven by pulmonary vascular and right ventricular myocardial remodelling, eventually leading to right heart failure (RHF) with a severely unfavourable prognosis. Cardiovascular remodelling is accompanied by an abundant re-expression of the extra-domain A of fibronectin (ED-A+ Fn), previously identified by our group as a crucial factor in the pathogenesis of PH in a mouse model of monocrotaline induced PH. We therefore aimed to elucidate its role in the development of hypoxia associated PH and consecutive RHF, depicting clinical group 3 (PH associated with lung diseases and/or hypoxia), by implementing the Sugen 5416/ Hypoxia (SuHx) mouse model of PH in a comparison of C57BL/6 ED-A+ Fn knockout (KO)* and wild-type (WT) mice.
Methods: PH in mice (n=26) was induced using the Sugen 5416/Hypoxia method. Subsequently, we examined 4 experimental groups: normoxic WT mice (WTNx, n=8), SuHx-induced PH in WT mice (WTSuHx, n=8), normoxic ED-A+ Fn KO mice (KONx, n=5) and SuHx-induced PH in ED-A+ Fn KO mice (KOSuHx, n=5). All animals underwent detailed echocardiographic evaluation of right ventricular (RV) morphology and function (e.g., basal RV diameter, RVbasal or tricuspid annular plane systolic excursion, TAPSE), right heart catheterization (RHC) to determine right ventricular systolic pressure (RVPsys) and histological tissue analyses.
Results: RHC displayed a significant elevation of RVPsys in WTSuHx (85.2±11.4mmHg) compared to WTNx (45.2±4.6mmHg, p=0.006), KONx (38.9±4mmHg, p=0.016) and KOSuHx (49.8±9.5mmHg, p=0.015) mice. Echocardiographic parameters were remarkably impaired in WTSuHx compared to all the other groups, e.g., with a significant increase in RVbasal (p=0.012) compared to KOSuHx mice. When compared to corresponding normoxic groups, histological evaluation revealed significant lung tissue damage after PH induction in both, WTSuHx (p=0.006) and KOSuHx (p=0.033). Moreover, the extent of lung tissue damage was significantly higher in the WTSuHx compared to KOSuHx group (p=0.01).
Conclusions: Apart from being a relevant pathogenetic factor in monocrotaline induced PH, our study demonstrates that ED-A+ Fn further exerts a pivotal function in the preclinical model of SuHx-induced PH. Thus, our results underline a certain role of the molecule also in clinical group 3 PH and consecutive RHF. Given the limited therapeutic options available, ED-A+ Fn qualifies as promising biomarker and therapeutic target capable of attenuating detrimental PH associated tissue remodelling, e.g., by administrating neutralizing antibodies.
*The ED-A+ Fn knockout mouse model was generated and generously provided by the International Centre for Genetic Engineering and Biotechnology (ICGEB, Dr. A. Muro) in Trieste, Italy