Abstract Body (Do not enter title and authors here): Background: Whether and how any anti-inflammatory agents and their combination with conventional pulmonary vasodilators protect against pulmonary arterial hypertension (PAH) is unknown. Hypothesis: The disruption of C-C motif chemokine receptor (CCR) -2, a receptor for CCL-2, ameliorates PAH in any models with the reversal of the associated pro-inflammatory state and vascular cell phenotypes and synergizes with any conventional pulmonary vasodilators. Methods and Results: By using Ccr2(-/-) rats generated by CRISPR/Cas9, we investigated PAH in Ccr2(+/+) or Ccr2(-/-) rats treated with monocrotaline (MCT), SU5416/hypoxia (SuHx), and chronic hypoxia (CH). Ccr2(-/-) decreased the right ventricular systolic pressure, right ventricular hypertrophy, and mortality rate, and reversed increased expression of inflammatory cytokines/chemokines (IL-6, TNF-α, CCL2, IL-1β, TGF-β) in MCT-treated rats, but not in SuHx or CH models. Consistently, Ccr2(-/-) decreased indices of pulmonary vascular diseases (PVDs) and perivascular macrophage infiltration, as well as reversed impaired BMPR2 signaling, increased endothelial apoptosis, impaired NO signaling (eNOS, peNOS/eNOS) and decreased phosphodiesterase (PDE)-5 expression in lungs in MCT-treated rats. Gene expression of the receptor for prostaglandin I₂ and endothelin was not altered in MCT-treated rats by Ccr2(-/-). In cultured pulmonary arterial smooth muscle cells (PASMCs), Ccr2(-/-) suppressed CCL2-induced hyperproliferation and dedifferentiation as well as reversed CCL2-induced decrease in PDE5 expression. Consistently, the whole-genome RNA sequencing analysis identified differentially expressed genes in CCL2-stimulated Ccr2(-/-) PASMCs, which are related to cellular differentiation and contraction. Based on studies in rats and cultured PASMCs, we investigated whether a PDE5 inhibitor, tadalafil, synergizes with Ccr2(-/-). Tadalafil administration ameliorated PH and PVDs in MCT-treated Ccr2(-/-) rats but not in Ccr2(+/+) rats, and further improved survival in Ccr2(-/-) rats. Conclusions: PDE5 inhibition synergized with Ccr2 disruption in protecting against PAH in MCT-treated rats, which was mechanistically related to the restoration of proinflammatory states and associated vascular cell phenotypes. These findings confer a fundamental basis supporting that CCR2 may be a therapeutic target in intractable PAH patients with a certain CCR2-related inflammatory phenotype and refractory to conventional pulmonary vasodilators.