To assess the effect of dl-3-n-butylphthalide (NBP) on angiogenesis and its underlying mechanism in a rat model of chronic myocardial ischemia (CMI).Forty Sprague-Dawley rats were randomly divided into four groups: model, low-dose NBP (L-NBP), middle-dose NBP (M-NBP), or high-dose NBP (H-NBP) (n=10/group). All groups received intraperitoneal injections of isoprinosine hydrochloride daily for 14 days. Additionally, the L-NBP, M-NBP, and H-NBP groups received NBP at 3, 6, and 12 mg per kg body weight, respectively, by intraperitoneal injection. An additional 10 rats (control group) received 0.9% sodium chloride via intraperitoneal injection for 14 consecutive days. Echocardiography was used for the measurement of heart function. Immunohistochemical staining for factor VIII-related antigen and microvascular density determination were performed. The protein and mRNA expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in CMI areas were measured by western blot and RT-PCR, respectively.Electrocardiograms showed that NBP improved cardiac function by regulating left ventricular end-diastolic and end-systolic diameters, ejection fraction, and fractional shortening. Compared with the control and model groups, the L-NBP, M-NBP, and H-NBP groups showed increased mRNA and protein expression of VEGFA and HIF-1α in myocardial tissue. The mRNA and protein expression of VEGFA and HIF-α in the H-NBP group were the highest.NBP treatment promotes VEGF and HIF-1α protein expression during myocardial ischemia, which may represent useful biomarkers for coronary collateral establishment and offer potential targets for therapeutic induction of angiogenesis in patients with CMI.AJTR Copyright © 2022.