## 3 Results  
### CAPE Increases the Release of VEGF from VSMCs  
Wound angiogenesis plays a critical role in the proliferative phase of healing [2; 24]. Moreover, studies have reported that VEGF is the main factor in angiogenesis processes, and is particularly associated with wound repair [24]. Therefore, the effect of CAPE on VEGF's dose-dependent release in human VSMCs was assessed. The exposure of VSMCs to CAPE for 24 h raised the basal release of VEGF, with significantly increased levels observed at doses >3 \(\upmu\)M, reaching approximately 441% at 30 \(\upmu\)M, which was comparable to the effect of platelet-derived growth factors (PDGF) at 30 ng/mL (Figure 1).  
CAPE Causes Endothelial-Dependent NO-Mediated Vasorelaxation and Inhibits U46619-Induced Vasoconstriction in Porcine Coronary Arteries  
It has previously been suggested that blood supply to foot ulcers in patients with diabetes is diminished owing to the decline in NO formation by vascular endothelial cells (ECs) [25]. Moreover, improved endothelium-dependent vasodilation has been shown to be associated with vascular repair and re-endothelialization in diabetic animal models [26]. Based on such reports, we conducted a vascular reactivity study to investigate the effect of CAPE on vascular function and subsequently elucidate the underlying mechanisms. The results showed that CAPE induced the relaxation of isolated porcine coronary artery rings with endothelium (but not of those without endothelium) in a concentration-dependent manner (Figure 2a). The relaxation responses were 12.9 \(\pm\) 4.6%, 34.7 \(\pm\) 8.2%, and 75.6 \(\pm\) 8.3% at concentrations of 3, 10, and 30 \(\upmu\)M, respectively. CAPE relaxation was also significantly reduced by N\({}^{\upmu\text{o}}\)-nitro-L-arginine (L-NA, a NO synthase inhibitor) and 1H-[1,2,4]oxadiazol[4,3-\(\upalpha\)]quinoxalin-1-one (ODQ), a guanylyl cyclase inhibitor. Alternatively, indomethacin (INDO), a cyclooxygenase inhibitor, and tetraethylammonium (TEA), a potassium channel blocker, did not inhibit the relaxation induced by CAPE (Figure 2b).  
Figure 1: The dose-dependent effect of CAPE on the expression of VEGF released from VSMCs. The level of VEGF was expressed as the percentage of VEGF levels at the control. The values were the mean \(\pm\) SEM of n = 3. * \(p\) < 0.05 vs. control.  
These findings indicate that CAPE-induced vasorelaxation of the porcine coronary artery rings depended on vascular endothelium, and was mainly mediated by the NO/cGMP pathway.  
Additionally, this study showed that CAPE inhibited U46619-induced contraction. As observed, the treatment of porcine coronary artery rings with 10 uM and 100 uM CAPE for 5 min before adding the increasing concentrations of U46619 attenuated the contractions significantly (Figure 3).  
Figure 3: The effect of CAPE on contractile responses. Intact rings were incubated with CAPE (10 and 100 uM) for 5 min before adding U46619 at increasing concentrations. The contraction response was expressed as the percentage of the U46619-induced contraction. Values were expressed as the mean \(\pm\) SEM (n = 3). * \(p<0.05\) vs. control.  
Figure 2: CAPE-induced vasorelaxation in porcine coronary artery rings. The relaxation response was expressed as the percentage relaxation of the U46619-induced contraction (100% represents complete relaxation). (**a**) CAPE’s concentration-dependent relaxation curves (0.3, 1, 3, 10, 30, and 100 uM) with and without endothelium. (**b**) CAPE’s concentration-dependent vasorelaxation curves (0.1, 0.3, 1, 3, 10, 30, and 100 uM) on U46619-induced vasocontration with pharmacological inhibitors. The pharmacological inhibitors L-NA (300 uM), indomethacin (10 uM), TEA (10 mM), and ODQ (10 uM) were treated for 30 min before U46619-induced contraction. Values were presented as the mean \(\pm\) SEM (n = 4). * \(p<0.05\) vs. (**a**) without endothelium or (**b**) control.