6. Conclusions

BMI and waist circumference. bFGF changes endothelial angiogenic properties [38]. The correlation between bFGF and MMPs in an endothelial culture medium suggests that the expression of MMPs is critical for the migration and invasiveness of cells in the formation of new blood vessels [39]. The significant lowering of bFGF in patients treated with a diet alone was probably one of the most important factors that contributed to the decreased migration and

Endostatin inhibits the proliferation, migration, adhesion and ability to form the tubes by altering the action of VEGF and bFGF. It blocks multiple signaling pathways (TNF-α, NF-κB, adhesion and clotting) [47]. The elevated endostatin concentrations are characteristic of overweight patients [37]. Eight weeks of moderate CR was enough to decrease endostatin concentration in both obese groups. It is worth to emphasize that endostatin was the only angiostatic

Ang-1 and Ang-2 control the maturation and stabilization of blood vessels [42, 48] and by that means regulate AT growth [48]. Dietary restrictions reduce their concentration [75]. Ang-1 was the only angiogenic parameter that was reduced in obese patients with GI. Since Ang-1 stimulates proliferation and migration, its reduced concentration after CR could also be responsible for diminished endothelial angiogenic function observed in vitro. Ang-2 is synthesized almost exclusively by ECs cells during vascular remodeling [103]. It destabilizes the vascular wall to facilitate the action of other pro-angiogenic factors [104]. The mechanism of angiopoietins' action is not fully understood. Ang-2 has dual pro- and anti-angiogenic properties. It is believed that Ang-2 acts via a Tie-2 receptor as its antagonist, when Ang-1 is not available or acts independently without a Tie-2 receptor [105]. Higher level of Ang-2 is observed in patients with type 2 diabetes [106] as a hyperglycemia effect [107]. It has been suggested that elevated concentrations of Ang-2 and hyperglycemia may promote abnormal neovascularization and endothelial dysfunction, which in turn leads to diabetic micro- and

IP-10 is a chemotactic factor for T cells, produced by various cells such as monocytes, ECs, fibroblasts, in response to IFN-γ stimulation [50]. Dalmas et al. show higher blood levels of IP-10 in obese patients, without any differences between diabetic and non-diabetic patients [52]. The group of obese patients with GI was characterized by a lower IP-10 (45%) at baseline. CR reduced the IP-10 concentration by 76% only in the normoglycemic obese. The 10-year followup of patients with type 2 diabetes in the MONICA/KORA clinical trial suggests that the IP-10 protein is one of the risk factors for the clinical development of diabetes [109] and its concen-

Infiltrating of immune cells in AT is an important factor leading to inflammation and IR [6] Interferon-γ is known to change the macrophage phenotype to more pro-inflammatory (M1) [53]. Patients with GI had a higher IFN-γ concentration after CR. Higher fat content and stronger stimulation by macrophage-derived IFN-γ were the important factors for higher concentrations of pro-inflammatory adipokines after the experiment (higher TNF-α after CR). Obese individuals usually have elevated IFN-γ levels, particularly patients with central obesity [54]. Diet intervention significantly decreased IFN-γ levels in the normoglycemic obese (74%). Although plasma concentrations of IP-10 and IFN-γ in the obese with GI after CR were significantly higher when compared with the normoglycemic obese, the diet did not change their concentrations. It is

tration could be lowered by CR and lifestyle modification [110].

invasiveness of EC after the intervention.

272 Endothelial Dysfunction - Old Concepts and New Challenges

macroangiopathy [108].

parameter modified by CR in obese patients with GI.

AT remodeling is pathologically accelerated in an obese state due to local hypoxia leading to reduced angiogenesis, severe immune cell infiltration with subsequent pro-inflammatory responses and additional deterioration of EC functions. It is believed that EC dysfunction in obesity can be reduced by CR. Moderate CR reflects a real-life situation and could be optimal to achieve an improvement in EC. Our observations suggest that a moderate CR can improve several parameters of EC function, especially those involved in angiogenesis. It also improves anthropometric and metabolic measurements, but does not significantly strengthen the antioxidant status. The in vitro model shows how various circulating factors, induced by CR, affect the endothelial proliferation, migration and invasiveness. This process is a result of a reduction of inflammation and a modification of angiogenic and angiostatic factors. Additionally, in patients with glucose intolerance, it is also caused by potential anti-angiogenic properties of metformin. The obtained results are particularly pronounced in the normoglycemic obese, and to a lesser extent in the obese with GI and IR, who may have an adverse impact on AT remodeling, the cardiovascular system and might have an increased risk of obesity-associated cancer diseases.
