Advanced-stage pulmonary arterial hypertension (asPAH) is characterized by endothelial dysfunction and fibrotic remodeling of pulmonary arterioles that promotes irreversible right heart failure. Thus, identifying mechanisms that regulate vascular fibrosis in early PAH (esPAH) may have translational importance. We hypothesized that profibrotic molecular pathways differentiate esPAH from asPAH. Male rats received monocrotaline (60 mg/kg; day 0) to induce inflammatory PAH. Cardiac catheterization and pulmonary artery endothelial cell (PAEC) transcriptomic analyses were performed on days 15 and 21 for esPAH and asPAH, respectively. The esPAH profile included: right ventricular-pulmonary arterial uncoupling (1.13 ± 0.05 vs. 0.90 ± 0.06, RV end-systolic elastance/PA elastance) and increased indexed pulmonary vascular resistance (50 ± 8 vs. 213 ± 29 mmHg*min*g-1*mL-1) without substantial elevation in PA systolic pressure (25 ± 1.2 vs. 33 ± 2.7 mmHg). Network medicine identified upregulation of c-terminal src kinase (Csk) as a mediator of PAEC fibrosis in esPAH but not asPAH in silico. Pulmonary endothelial expression of Csk protein by immunofluorescence correlated with vascular collagen (r=+0.87). To validate these findings in vitro, human PAECs (HPAEC) were treated with an inflammatory stimulus of lipopolysaccharide/interferon-Î³/interleukin-1Î² or vehicle control (V). Compared to V-control, inflammation increased Csk protein and mRNA expression by 2.3- and 2.0-fold, respectively. Inflammation also increased HPAEC hydroxyproline, an indicator of collagen abundance, by 3.1-fold vs. V-treated cells. Csk overexpression attenuated inflammation-mediated hydroxyproline accumulation by 84%. Impaired Csk may underlie HPAEC fibrosis in esPAH, which, in turn, may have potential therapeutic implications for the prevention of fibrotic vascular remodeling and PAH progression.