**4.1 Role of VEGF in appendicitis**

Appendicitis is the most well-known gastrointestinal emergency and requires surgical approach in the pediatric population. The negative appendectomy rate is 8.4%, however largely higher among children aged <6 years at 56.7%. However, the diagnosis of appendicitis in children is often missed due even in a total examination. This article summarizes the current evidence on the influences of folic acid (FA) and vascular endothelial growth factor (VEGF) in appendicitis. The pathological processes of appendicitis could be approached by histopathological examination of microvessel thickness. Further analysis reveals that folic acid (FA) assumed a role in mucosal opposition and its capacity to recover, and VEGF (explicitly found in vein endothelial cells) was associated in tissue remodeling through a cycle of neovascularization, reepithelization, and guide of extracellular framework and has an important pro-angiogenic activity, having a mitogenic and an anti-apoptotic effect on endothelial cells, increasing the vascular permeability, promoting cell migration, etc. Due to these effects, it actively contributes in regulating the normal and pathological angiogenic processes [29].

Both folate acid and VEGF had a role as mentioned previously by certain cascades in the endothelial cells which may increase endothelial proliferation and induces branching of new collaterals during inflammation. This mechanism ensure enough and adequate blood flow locally around the appendix. The VEGF-induced proliferation among the endothelial cells adapts to race cell damages from stretch, cytokine induced cell death, and increase intraluminal pressures. This means collateral vascularization in the appendix were stabilized and able to receive more blood flow for tissue healing process. This puts VEGF has a special role in preventing tissue damage and the complication of appendicitis such as perforation or necrosis [35].

Folate acids had been widely concentrated in cardiovascular sickness and malignancy and an increased risk of infection among patients with insufficient degrees of folate acid. A low folate acid serum and raised homocysteine was shown to be found among patients with constant provocative infections and conditions such as systemic inflammatory illness and endothelial damage. A higher folate level would prevent endothelial damage as it would help maintain levels of homocysteine, vasodilators, and nitric oxide [28, 29, 36].

Similar patterns of reduction were also observed in basal VEGF levels among patients with appendicitis as reported by Fikri et al*.* However, the lower level in both FA and VEGF among patients with appendicitis were significant compared to control and a possible indicator in diagnosing complicated appendicitis. Another studies had reported increases in VEGF levels, namely in myocardial localized necrosis and was related to incendiary cytokines. The increasing levels of VEGF was directly associated with the number of hypoxia-inducible factors as it regulated the advancements of angiogenesis, vascular patency in atherogenic vessels. Fikri et al. further explained that VEGF levels in appendicitis has similar pattern as increase of VEGF during the stable phases after myocardial infarction and hence signifying that VEGF as a part of an ongoing inflammatory activity. The lower levels of VEGF often signifies a worsened condition and could be associated with a more complicated case of appendicitis [28, 36].
