Cardiovasc Diagn Ther. 2026 Apr 24;16(2):17. doi: 10.21037/cdt-2025-443. Epub 2026 Mar 27.
ABSTRACT
BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous condition with diverse aetiologies and clinical presentations, driven by remodelling of the pulmonary vasculature and right ventricular (RV) myocardium, progressing to right heart failure (RHF) with poor prognosis. Cardiovascular remodelling is characterized by re-expression of extra-domain A containing fibronectin (ED-A+ Fn), which our prior studies identified as a key pathogenetic mediator in monocrotaline-induced PH. This study investigated the role of ED-A+ Fn in the progression of hypoxia-associated PH and subsequent RHF, corresponding to clinical group 3 PH, associated with lung diseases and/or hypoxia. We employed the mouse model of Sugen5416/hypoxia (SuHx) induced PH, that reproduces essential features of both group 1 (pulmonary arterial hypertension) and 3 PH, comparing ED-A+ Fn knockout (KO) mice with wild-type (WT) controls (strain: Black 6, C57BL/6).
METHODS: PH was induced in male mice (n=26) employing the Sugen5416/hypoxia model. Animals were allocated to four experimental groups: normoxic WT controls (WTNx, n=8), WT mice with SuHx-induced PH (WTSuHx, n=8), normoxic ED-A+ Fn KO controls (KONx, n=5) and ED-A+ Fn KO mice with SuHx-induced PH (KOSuHx, n=5). Echocardiographic assessment of RV morphological structure and function was conducted, including measurements of basal RV diameter (RVbasal), right atrial (RA) area (RAarea), tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC). Right heart catheterization (RHC) was performed to measure RV systolic pressure (RVPsys), followed by histological and immunohistochemical analyses of tissue samples.
RESULTS: RHC demonstrated a significant increase in RVPsys in WTSuHx mice (85.2±11.4 mmHg) as opposed to WTNx (45.2±4.6 mmHg, P=0.006), KONx (38.9±4 mmHg, P=0.02) and KOSuHx (49.8±9.5 mmHg, P=0.02). Echocardiographic assessment revealed significant impairment in WTSuHx mice, including a markedly increased RVbasal (2.57±0.15 mm, P=0.01) relative to KOSuHx mice (2.14±0.19 mm). Histological analysis showed pronounced pulmonary tissue damage induced by PH in WTSuHx (5.63±0.7, P=0.006) and KOSuHx (2.7±0.98, P=0.03) compared to their respective normoxic controls, with significantly greater impairment observed in WTSuHx versus KOSuHx (P=0.01). The degree of RV myocardial injury was markedly greater in WTSuHx (0.88±0.41) versus WTNx (0.06±0.17, P=0.006), while KO groups displayed no significant differences. Pulmonary vasculopathy and immune cell infiltration, assessed by immunohistochemical analysis, were significantly exacerbated in WTSuHx relative to all other experimental groups.
CONCLUSIONS: Beyond its established pathogenetic role in monocrotaline-induced PH, our study additionally identifies ED-A+ Fn as a critical mediator in the preclinical SuHx model of PH. These findings underscore the involvement of ED-A+ Fn in both clinical group 1 and group 3 of PH, as well as in subsequent development of RHF. Given the limited availability of effective therapies, ED-A+ Fn represents a promising biomarker and therapeutic target, with potential of mitigating deleterious PH-mediated tissue remodelling, for instance, through administration of specific neutralizing antibodies.
PMID:42164742 | PMC:PMC13184926 | DOI:10.21037/cdt-2025-443