Background and Aims: Development and progression of Pulmonary Hypertension (PH), at least of the groups 1 (Pulmonary Arterial Hypertension), 2 (PH associated with left heart disease) and 3 (PH associated with lung disease), are accompanied by comparable patterns of pulmonary vascular and right ventricular tissue remodelling. These processes include an abundant re-expression of extra-domain A containing fibronectin (ED-A⁺ Fn) with spatial association to vessel structures and fibrosis. Since it is virtually absent in healthy adult organs, ED-A⁺ Fn qualifies as an excellent diagnostic marker or therapeutic target. Nevertheless, its functional role in PH pathogenesis remains unclear. The human recombinant antibody F8 (IgG format) specifically recognises ED-A⁺ Fn and shows functional blocking activity in vitro. Thus, F8 might serve as a novel therapeutic agent for diseases linked to an ED-A⁺ Fn re-expression.

Methods: PH was induced using the Monocrotaline (MCT) approach (PH mice). In total, 69 animals were included in the study approach and were divided into the following experimental groups: sham-treated WT controls (n=7), sham-treated KO controls (n=7),  PH mice without a specific treatment (WT: n=12; KO: n=10), PH mice treated with the dual endothelin receptor antagonist Macitentan (MAC; WT: n=6; KO: n=11), WT PH mice treated with the F8 antibody (n=8) and WT PH mice treated with an antibody of irrelevant antigen specificity in the murine system (KSF, n=8). Treatment effects were evaluated on the haemodynamic, echocardiographic and microscopic level.

Results: Compared to sham-treated WT controls, the WT PH mice showed a significant elevation of the right ventricular systolic pressure (RVP_sys, p<0.05) as well as alterations of various echocardiographic parameters, including the basal right ventricular (RV_basal, p=0.016) diameter and tricuspid annular plane systolic excursion (TAPSE, p=0.008), reflecting an impairment of RV function. None of these detrimental effects were observable within the KO PH mice compared to controls (p=n.s. for all parameters). In WT PH mice treated with the F8 antibody, haemodynamic and echocardiographic parameters were significantly improved compared to untreated WT PH mice or those treated with the KSF antibody (p<0.05 for the majority of parameters). Histological evaluation revealed significant lung tissue damage after PH induction in both, WT and KO PH mice (p=0.008), which could be reduced after to F8 treatment in WT PH mice (p=0.04). Additionally, KO PH mice showed significantly less tissue damage compared to the WT PH mice (p=0.008).