Vascular Endothelial Growth Factor (VEGF) ROLE IN ENDOTHELIAL DYSFUNCTION MECHANISMS AND ARTERIAL PRESSURE CONTROL

Aims of the study: evaluating the Vascular Endhitelial Growth Factor (VEGF) effect on systemic blood preassure and machanisms of regulation oxid nitric induced. 3 studies were been conducted:1) Aims of the first study: evaluating in vitro role of VEGF and lycopene, present in tomato fruit, on endothelial cells, using Human umbilical vein endothelial cells (HUVECs).Materials and methods: HUVECs were been incubated with lycopene (2μM), VEGF and L-NAME were observed by confocal microscopy the NO production in terms of fluorescence intensity (DAF) have been evaluated. Results: the DAF was higher in HUVECS incubated with lycopene (381,1 ± 126,99, p < 0,05 , n = 24 ) compared with control (292,6 ± 107,24 , n = 24); when cells were incubated with VEGF (10ng/ml) the intensity of fluorescence significantly increased (449,7 ± 115,64 p <0,05 , n=8). The supernatant of HUVECs incubated with lycopene showed the highest amounts of nitrate–nitrit. Conclusions: The study shows that the main component of tomato has important biological properties such as preservere endothelial function. Lycopene has been shown to positively modulate the production of intracellular NO.2) Aims of second study: testing whether a 7-day period of tomato paste supplementation can improve some haemodynamic parameters in healthy volunteers (HV) before and after a standardized fat meal.Methods and results: We enrolled 19 male HV in a randomized, single-blind (operator), crossover design. HV maintained a diet poor in vegetables during the study periods, starting a week before randomization. They were randomized either to a supplementation arm (70 g tomato paste per day) for 7 days or to a control arm (no added tomato paste) with a two-week washout periods between the different periods. Flow-Mediated Dilatation (FMD) and Carotid Distendibility (CD) by ultrasounds, Stiffness Index (SI), Reflection Index (RI) by photopletismography and blood pressure (BP), were measured as an estimate of vascular function before and after (2 and 3.5 hours) the fat meal. In the direct comparison between the 2 arms, only the difference in SI was increased in the without-tomato-arm as compared to the tomato-arm both at 2 and 3.5h points (Δ-mean [95%CI]: +0.46m/sec [0.01/0.93] m/sec, +0.55 [0.03/1.07m/sec], P<0.05). After the fat meal, in both arms, HV showed a marked reduction in RI at 2h (-10.7%[-6.7/-14.7%] with tomato paste; -7.2%[-3.0/-11.4%] without tomato paste; P<0.01). Interestingly, only in the tomato-arm, some haemodynamic changes were detectable at 2h with respect to baseline: in particular an increase in brachial artery diameter (+0.20mm[0.06/0.33mm], P<0.01), a reduction in diastolic BP (-2.4 mmHg[0.1/4.7 mmHg], P<0.05) and an increase in heart rate (+3.9bpm [1.4/6.4bpm], P<0.01). The same parameters were not significantly changed in the without-tomato-arm even if they resulted not significantly different between the two arms. The nitrites were higher il tomato group vs placebo one (85, 7 ± 42,2 vs 122,5 ± 83,4 p= 0,05)Conclusion: Tomato supplementation modifies some haemodynamic parameters triggered by a high fat diet suggesting a possible beneficial effect in people assuming a diet rich in tomato.3) Aims of the third study: evaluating the effect of antiangiogenitic drugs (antiVEGF/VEGFR) used in first line therapy in clear cellular carcinoma (CCR) on BP incidence, endothelial function, arterial rigidity and microvascular enviroment. Methods and results: We enrolled 19 hypertensive controlled/normotensive patients candidated to use antiangiogionetic drugs. Vascular test (flow mediated dilatation, carotid distensibility, capillaroscopy and BP) were measured at baseline (time 0 or T0), after 1 month of therapy (Time 1 or T1) and after 3 months of therapy (Time 2 or T2). We demonstrated an increase of BP in 47% of patients at time T1. We divided the population in two groups (patients with no preassure increase at T1 and patients with pressure increase at T1). At baseline population present some differences in particular levels of preassure (PAS 141,5±14,2 vs 123,1 ±11,9 p=0,008 e PAD 87,4±8,6 vs 77,7±8,0; p= 0,002), nitrates (no BP T1 92,7±46 vs BP T1 125±92 uM/mmol) and PLTs (no BP T1 218±56,8 and BP T1442±273,5; p =0,016). We documented a linear correlation betwen preassure increase and riduction in carotid distensibility at T1 (r=-0,52; p<0,05). The capillaroscopy was modified in 53% of patients after 1 month of therapy but with no significant differences in the two groups. Conclusion: the antiVGF therapy in our population determined an increase in BP and a modification in vassels structure tested with capillaroscopy. Although there were no correlations between preassure and capillary modifications. All those mechanisms can explain the important role of VEGF in blood preassure control. No direct correlation was identified between vascular caratheristics and cancer evolution.