## 4 Discussion  
VEGF plays an important role in vascular remodeling and immune processes in periapical diseases [26]. Furthermore, it participates in both the initiation and progression of periodontal inflammation and in the healing of periodontal diseases [7]. Many inflammatory cytokines have a significant effect on angiogenesis, as they upregulate or downregulate VEGF expression. Overexpression of VEGF in many diseases induces more severe inflammation. The recruitment of inflammatory cells is important in the pathogenesis of chronic periapical periodontitis, a disease with long-term consequences that result in damaged supporting tissues, including alveolar bone resorption around the apical region and formation of inflamed periapical tissue with an elevated number of inflammatory cells [27]. In patients with periodontitis, VEGF levels are higher in diseased periodontal tissue than in clinically healthy tissue. VEGF mRNA expression is significantly greater in periapical granulomas than in healthy gingival tissues [28]. VEGF has a fundamental role in the progression of periodontal disease, and VEGF levels are correlated with severity of periodontitis [29]. Bone remodeling is also a dynamic balance between two processes: bone removal by osteoclasts and new bone formation by osteoblasts. VEGF regulates bone remodeling by stimulating osteoblast differentiation [30]. According to [PERSON] et al., VEGF may be involved in osteocl differentiation and in intensification of osteocl bone-resorbing activity [31]. Previous studies indicate [32; 33; 34] that blocking VEGF activity in chronic inflamed tissue may inhibit disease progression. In the present study, pharmacotherapy decreased VEGF concentrations in periapical inflamed tissues. Moreover, lowering VEGF levels with systemic NSAIDs and antibiotics may diminish the development of inflammatory granulomatousous tissue formation. Unfortunately, VEGF levels that are either too high or too low may have negative consequences. [PERSON] et al. [35] found that diminished production of VEGF leads to decreased angiogenesis, a common reason for impaired tissue repair. VEGF acts as an endothelial cell mitogen, chemotactic agent and inducer of vascular permeability. VEGF is essential for \begin{table}
\begin{tabular}{c c c} \hline \hline
**Group** & **\(n\)** &
\begin{tabular}{c} **VEGF Concentration (ng/mL)** \\ **Mean \(\pm\) SD** \\ \end{tabular} \\ \hline
0 & 25 & 10.4324 \(\pm\) 4257.2 \\ I & 7 & 6.0967 \(\pm\) 1929.6 * \\ II & 5 & 5.6609 \(\pm\) 2394.9 * \\ III & 5 & 7.1419 \(\pm\) 2600.8 * \\ \hline \hline \end{tabular}  
* 0 vs. I \(p\) = 0.008,
* 0 vs. II \(p\) = \(<\)0.01,
* 0 vs. III \(p\) = \(<\)0.07.  
\end{table} 
Table 1: Differences of VEGF concentration among tested groups and the control group. Figure 3: VEGF concentration in all groups of patients: group I (NSAIDs), group II (antibiotics), group II (NSAID and antibiotics) and control group (no drug treatment). normal tissue repair because of its effects on multiple components of the wound healing cascade, including collagen deposition, angiogenesis and epithelization. VEGF seems to activate mononuclear cells and promote the closure of nonhealing skin ulcers [36; 37]. [PERSON] et al. [35] suggest that topical VEGF may improve healing by mobilizing bone marrow-derived cells and up-regulating factors. Unfortunately, many questions about the complex nature of angiogenesis, granulation tissue formation, bone resorption and bone healing induced by VEGF in chronic periapical periodontitis remain unanswered. Systemic or local antibiotics may be applied according to the severity of the patient's signs and symptoms [38]. For the short-term treatment of an acute or locally persistent periodontal infection, systemic antibiotics that thwart pathogenic microorganisms are indicated [39]. Although the presence of periodontal pathogens is essential for the onset of periodontitis, these organisms do not sustain disease progression. In fact, the host immune response modulates the disease toward destruction or healing [40].