Laura Tempel, Andrea Schrepper, Alexander Berndt, P Christian Schulze, Marcus Franz, Katja Grün
Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling and increasing right ventricular (RV) afterload. Extracellular matrix (ECM) remodeling is central to PH, but its temporal dynamics across lung and RV tissue remains insufficiently defined. Extra domain A-containing fibronectin (ED-A+ Fn) is a fetal fibronectin splice variant re-expressed during tissue injury and chronic inflammation. This study investigated temporal and spatial ED-A+ Fn expression in monocrotaline (MCT)-induced PH in rats. Male Sprague-Dawley rats were analyzed at day 7, 14, 21, and 28 after MCT injection. Disease progression was assessed by echocardiography, right heart catheterization, histology, immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and serum enzyme-linked immunosorbent assay (ELISA). MCT induced PH with increasing RV systolic pressure, RV dilatation, reduced tricuspid annular plane systolic excursion (TAPSE), and worsening pulmonary and myocardial tissue damage. ED-A+ Fn was nearly absent in controls but increased progressively at the protein level in lung and RV tissue. Significant upregulation was detected from day 14 onward in the lung and at later stages in the RV. ED-A+ Fn was spatially associated with macrophage accumulation and remodeling markers, including α-smooth muscle actin and tenascin-C. By contrast, ED-A+ Fn messenger RNA (mRNA) levels did not change significantly. Circulating ED-A+ Fn was increased in PH animals and correlated with impaired RV function, higher RV systolic pressure, and pulmonary and RV myocardial histopathological damage. ED-A+ Fn is progressively re-expressed during experimental PH and reflects cardiopulmonary remodeling in tissue and circulation. These findings support ED-A+ Fn as a dynamic biomarker of disease progression and a potential translational target in PH.