β‐sitosterol Alleviates Pulmonary Arterial Hypertension in Rats With Involvement of the VEGF/PI3K/AKT Signaling Pathway

ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive and lethal disorder with limited therapeutic options. β‐sitosterol, a plant compound, has shown potential in managing PAH, but its protective mechanisms remain unclear. We evaluated the protective effects of β‐sitosterol against monocrotaline (MCT)‐induced PAH in rats and explored the underlying mechanisms. First, network pharmacology was used to predict potential targets of β‐sitosterol in PAH. A rat model of PAH was established by a single subcutaneous injection of MCT (60 mg/kg). From day 28 after MCT injection, PAH rats were treated with β‐sitosterol (100 mg/kg/day) by gavage for 28 days. Histopathological analysis, RT‐qPCR, and Western blotting were performed to evaluate inflammatory infiltration, cellular proliferation, apoptosis, and the activity of the VEGF/PI3K/AKT pathway in lung tissues. Network pharmacology analysis identified the VEGF/PI3K/AKT pathway as centrally implicated. In vivo , β‐sitosterol treatment significantly improved hemodynamic parameters and right ventricular function, reducing pulmonary vascular remodeling. Furthermore, β‐sitosterol suppressed vascular inflammation and proliferation while promoting apoptosis. RT‐qPCR analysis revealed that β‐sitosterol significantly reduced mRNA levels of VEGF, TNF‐α, IL‐6, IL‐1β, Collagen I, and TGF‐β1 compared with the MCT group. Western blotting demonstrated that β‐sitosterol decreased the phosphorylation of VEGFR2, PI3K and AKT, upregulated Bax expression, and downregulated PCNA and Bcl‐2. In conclusion, β‐sitosterol may alleviate PAH with the involvement of the VEGF/PI3K/AKT signaling pathway. These findings suggest the therapeutic potential of β‐sitosterol against PAH and offer preliminary insights into its molecular mechanisms.