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

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.