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The introduction of Vascular Endothelial Growth Factor (VEGF) signaling pathway inhibitor treatment has highlighted the role of the baseline activity of the VEFG system for blood pressure regulation. VEGF signaling pathway is associated with hypertension and proteinuria. Activation of the endothelin system, endothelial dysfunction and capillary rarefaction are among the underlying mechanisms possibly explaining the rise in blood pressure and, to some extent, also the renal injury. The hypertension induced by VEGF signaling pathway inhibition is, usually, responsive to treatment. Recommendations about the management of cardiovascular toxicity in patients receiving VEGF signaling pathway inhibitors include a formal cardiovascular risk assessment before initiation of VEGF signaling pathway inhibitor treatment, active monitoring of blood pressure and cardiac toxicity throughout treatment, with more frequent monitoring during the first cycles of therapy, given that marked and unpredictable blood pressure rises can occur early after treatment with a VEGF signaling pathway inhibitor, and aggressive management of blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications. In patients with preexisting hypertension, the blood pressure target for initiating VEGF signaling pathway inhibitor treatment should be <140/90 mmHg. Blockers of the renin-angiotensin system and calcium channel antagonists are among the drugs to be preferably used in these clinical conditions.

The possible relationships between indicators of small resistance artery structure and of arterial stiffness and central hemodynamics have not yet been evaluated. Aim of this study was to assess the relationship between indicators of large arteries stiffness, including carotido-femoral pulse wave velocity and of vascular alterations in small resistance arteries (media/lumen ratio, M/L) in patients with primary and secondary hypertension. In 73 patients (mean age, 53±14 years, 34 females, 25 with type 2 diabetes mellitus, 18 never treated) with essential (n=37) and secondary (n=36) hypertension, carotido-femoral pulse wave velocity was measured. In all patients, small resistance arteries were dissected from subcutaneous fat biopsies and mounted on an isometric myograph, for the measurement of the M/L. Pulse wave analysis was performed in 67 patients. M/L ratio was significantly related to brachial systolic blood pressure and pulse pressure (r=0.36 and 0.31, P<0.001, respectively) and to central systolic and pulse pressure (r=0.44 and 0.42, P<0.001, respectively). A positive correlation was observed between M/L ratio and carotido-femoral pulse wave velocity (r=0.45; P<0.001); this correlation remained statistically significant after adjustment for age and mean blood pressure. M/L ratio was also associated to aortic augmentation index (r=0.33; P=0.008), and this correlations remained statistically significant after adjustment for potential confounders. In hypertensive patients, the presence of structural alterations of small resistance arteries may be associated with the increase in large arteries stiffness and possibly contribute to an increase in central pressure by increasing the magnitude of wave reflections.

Objectives: It has been previously demonstrated that the morning rise (MoR) of blood pressure (BP) may predict major cardiovascular events in hypertensive patients. Structural alterations of small resistance arteries, as evaluated by the tunica media to internal lumen ratio (M/L) of subcutaneous small resistance arteries, may also predict cardiovascular events. Because an increased M/L may amplify the effect of hypertensive stimuli, the present study aimed to evaluate the possible relationships between MoR and M/L in a population of hypertensive patients., Methods: Sixty-four patients with essential hypertension were included in the present study. All patients were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on an isometric myograph, and the M/L was measured. In addition, MoR was calculated from ambulatory blood pressure monitoring (ABPM) according to four previously published different methods (MoR1 to MoR4)., Results: A statistically significant correlation was observed between M/L and MoR1 (r = 0.52, P < 0.001), MoR2 (r = 0.32, P < 0.01), MoR3 (r = 0.25, P < 0.05) and MoR4 (r = 0.27, P < 0.05), as well as between internal diameter of subcutaneous small arteries and MoR1 (r = -0.45, P < 0.001) and MoR2 (r = -0.28, P < 0.05)., Conclusion: Our results indicate that subcutaneous small artery structure is related to MoR, possibly because an altered vascular structure may amplify BP changes or, vice versa, because a greater MoR may further damage peripheral vasculature.

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.

Objective: It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. Design and methods: We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes. Results: A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells. Conclusion: In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients. [ABSTRACT FROM AUTHOR]

BACKGROUND Different components of the immune system, including innate and adaptive immunity (T-effector lymphocytes and T-regulatory lymphocytes-- TREGs) may be involved in the development of hypertension. In addition, it was demonstrated in animal models that TREGs may prevent angiotensin II-induced hypertension and vascular injury/inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular structural alterations. METHODS For this purpose, in the present study, we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph and the media to lumen ratio (M/L) was calculated. In addition, retinal arteriolar structure was evaluated noninvasively by scanning laser Doppler flowmetry. Capillary density in the nailfold, dorsum of the finger, and forearm were evaluated by videomicroscopy. A peripheral blood sample was obtained before surgery for assessment of T-lymphocyte subpopulations by flow cytometry. RESULTS Significant negative correlations were observed between indices of microvascular structure (M/L of subcutaneous small arteries and wall to lumen ratio of retinal arterioles) and circulating TREG lymphocytes. A direct correlation was observed between M/L of subcutaneous small arteries and circulating Th17 lymphocytes. In addition, total capillary density was correlated with a TREG effector memory subpopulation. CONCLUSION Our data suggest that some lymphocyte subpopulations may be related to microvascular remodeling, confirming previous animal data, and opening therapeutic possibilities. [ABSTRACT FROM AUTHOR]

It is not known whether, in obesity, the capillary density or the number of circulating endothelial progenitor cells (EPCs) are reduced, or whether fibrosis of small vessels is also present. In addition, possible effects of weight reduction on these parameters have never been evaluated. Therefore, we investigated EPCs and capillary density in 25 patients with severe obesity, all submitted to bariatric surgery, and in 18 normotensive lean subjects and 12 hypertensive lean patients as controls. All patients underwent a biopsy of subcutaneous fat during bariatric surgery. In five patients, a second biopsy was obtained after consistent weight loss, about 1 year later, during a surgical intervention for abdominoplasty. EPCs and capillary density were reduced in obesity, and EPCs were significantly increased after weight reduction. Vascular collagen content was clearly increased in obese patients. No significant difference in vascular collagen was observed between normotensive obese patients and hypertensive obese patients. After pronounced weight reduction, collagen content was nearly normalized. No difference in stress-strain relation was observed among groups or before and after weight loss. In conclusion, our data suggest that microvascular rarefaction occurs in obesity. EPCs were significantly reduced in obese patients. Pronounced weight loss induced by bariatric surgery seems to induce a significant improvement of EPC number, but not of capillary rarefaction. A pronounced fibrosis of subcutaneous small resistance arteries is present in obese patients, regardless of the presence of increased blood pressure values. Consistent weight loss induced by bariatric surgery may induce an almost complete regression of microvascular fibrosis. [ABSTRACT FROM AUTHOR]

It has been reported that the number of circulating endothelial progenitor cells (EPCs) reflects the endogenous vascular repair ability, with the EPCs pool declining in the presence of cardiovascular risk factors. However, their relationship with hypertension and the effects of anti-hypertensive treatment remain unclear. We randomized 29 patients with mild essential hypertension to receive barnidipine up to 20 mg or hydrochlorothiazide (HCT) up to 25 mg. Circulating EPCs were isolated from peripheral blood at baseline and after 3 and 6 months of treatment. Mononuclear cells were cultured with endothelial basal medium supplemented with EGM SingleQuots. EPCs were identified by positive double staining for both FITC-labeled Ulex europaeus agglutinin I and Dil-labeled acethylated low-density lipoprotein. After 3 and 6 months of treatment, systolic and diastolic blood pressure (BP) were significantly reduced. No difference was observed between drugs. An increase in the number of EPCs was observed after 3 and 6 months of anti-hypertensive treatment ( p < 0.05). Barnidipine significantly increased EPCs after 3 and 6 months of treatment, whereas no effect was observed with HCT. No statistically significant correlation was observed between EPCs and clinical BP values. Our data suggest that antihypertensive treatment may increase the number of EPCs. However, we observed a different effect of barnidipine and HCT on EPCs, suggesting that, beyond its BP lowering effect, barnidipine may elicit additional beneficial properties, related to a healthier vasculature. [ABSTRACT FROM AUTHOR]

Abstract: Macrovasculature and microvasculature are interrelated, and may influence each other. Microvascular structure is not only the site of vascular resistance but probably also the origin of most of the wave reflections generating increased central systolic blood pressure. Some index of large artery stiffness seems to be related with the media to lumen ratio of subcutaneous small resistance arteries of hypertensive patients. In addition, both microvascular structural alterations and changes in the mechanical properties of large arteries represent potent predictors of prognosis. In addition, drugs that may improve microvascular structure may also correct alterations in the mechanical properties of large arteries In fact, while β-blocking agents and diuretics have a negligible effect on microvascular structure, renin-angiotensin system antagonists and calcium entry blockers have favorable actions, improving also large artery mechanics and possibly reducing central wave reflections. [ABSTRACT FROM AUTHOR]

BackgroundIt has been suggested that in animal models, red wine may have a protective effect on the vascular endothelium. However, it is not known whether this effect is also present in human small vessels and whether it is specific for certain wines. The objective of this study is to compare the vasodilator effects in subcutaneous small resistance arteries of wines with different flavonoid content as well as of ethanol vs. wines in normotensive (NT) subjects and in patients with essential hypertension (EH).MethodsTwenty-six EH and 27 NT were included in the study. Subcutaneous small resistance arteries were dissected and mounted on a micromyograph. Then we evaluated vasodilator responses as concentration–response curves (20, 30, and 50 µl) to the following items: (i) a red wine produced in small oak barrels (“en barrique”: EB) (Barolo Oberto 1994), (ii) a red wine produced in large wood barrels (LB) (Barolo Scarzello 1989), (iii) a red wine produced in steel tanks (Albarello Rosso del Salento 1997), and (iv) a white wine produced in steel tanks in the presence or absence of an inhibitor of the nitric oxide (NO) synthase (L-NMMA 100 µmol/l).ResultsA dose-dependent vasodilator effect of red wines (particularly EB and LB) was detected in both NT and HT. The observed response was not reduced after preincubation with L-NMMA.ConclusionsOur results suggest red wines are more potent vasodilator than ethanol alone, possibly depending on the content of polyphenols or tannic acid. HT show similar responses compared with NT, indicating that red wine is not harmful in this population.American Journal of Hypertension 2010; doi:10.1038/ajh.2009.280 [ABSTRACT FROM AUTHOR]

Macrovasculature and microvasculature are deeply interrelated, since microvascular structure is not only the site of vascular resistance but probably also the origin of most of the wave reflections generating increased central systolic blood pressure. In fact, preliminary data suggest that some index of large artery stiffness is related with the media to lumen ratio of subcutaneous small resistance arteries of hypertensive patients. Microvascular structural alterations and changes in the mechanical properties of the macrovessels represent potent predictors of prognosis. Hypertension-related damage to the micro- and macrovascular system may be corrected by pharmacological agents. Among them, beta-blocking agents and diuretics have a negligible effect on microvascular structure, while renin-angiotensin system antagonists and calcium entry blockers have favorable actions, improving large artery mechanics and possibly reducing central wave reflections. [ABSTRACT FROM AUTHOR]

Objective. It has been previously demonstrated that structural alterations of subcutaneous small resistance arteries of hypertensive patients, as indicated by an increased media to lumen (M/L) ratio, is the most potent predictor of cardiovascular events. The aim of the present study was to identify possible determinants of small resistance artery structure that may be evaluated with non-invasive approaches. Materials and methods. One hundred and ninety-nine subjects (normotensives, essential hypertensives and patients with secondary hypertension) were included in the present study. All subjects were submitted to a biopsy of subcutaneous fat from the gluteal or the anterior abdominal region. Small resistance arteries were dissected and mounted on an isometric myograph, and M/L ratio was measured. All patients underwent standard biochemical tests, clinic blood pressure measurement, standard echocardiography and 24-h ambulatory blood pressure measurement. Glomerular filtration rate (GFR) was calculated according to MDRD study formula and Cockroft's formula. Results. Significant correlation was found between M/L ratio and, respectively: GFR calculated both with MDRD study formula and Cockroft-Gault formula, creatinine serum, blood urea nitrogen, glycaemia, circulating sodium, clinical pulse pressure, stroke volume to pulse pressure ratio, clinical systolic, diastolic and mean arterial pressure, daytime pulse pressure. However, in a multivariate regression analysis, only serum creatinine remained in the model, and proved to be an independent predictor of small artery structure. Conclusions. Indices of renal function and, probably, of large artery distensibility may be related to small arteries remodelling in hypertension. [ABSTRACT FROM AUTHOR]

We have evaluated the effects of different doses of an angiotensin-converting enzyme (ACE) inhibitor, enalapril (ENA) and of an angiotensin II type 1 receptor blocker olmesartan (OLM), on extracellular matrix of the heart, kidney, aorta and mesenteric artery of spontaneously hypertensive rats (SHR). Forty SHR and eight Wistar–Kyoto controls (WKY) were included in the study. Eight SHR were treated with high-dose OLM 15 mg/kg per day, eight with high-dose ENA 25 mg/kg per day, eight with low-dose OLM 1 mg/kg per day and eight with low-dose ENA (2 mg/kg per day). Eight SHR and eight WKY were kept untreated as controls. Treatment was from age 4 to 12 weeks. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) was measured, and the cardiac, aortic and glomerular interstitial collagen content was evaluated using Sirius red staining and image analysis. Mesenteric small arteries were dissected and mounted on a micromyograph, and the media:lumen ratio (M/L) was calculated. Collagen subtypes were evaluated by polarized light microscopy. The SHR treated with high-dose OLM or ENA showed a normalization of SBP. The RLVM was significantly increased in untreated SHR compared with untreated WKY, whereas significantly lower values were observed in the groups of SHR treated with high-dose OLM or ENA. A significant increase in cardiac and glomerular collagen content was observed in untreated SHR. Both high- or low-dose OLM and ENA normalized collagen content in the heart and the kidney. Both high-dose OLM and high-dose ENA normalized M/L ratio; however, OLM proved to be more effective than ENA in normalizing collagen pattern. In fact, aortic collagen content was normalized by both high-dose and low-dose OLM, but only by high-dose ENA. In conclusion, both OLM and ENA were significantly and equally effective in the prevention of cardiac and renal damage in SHR, whereas OLM was more effective than ENA in terms of effects on vascular extracellular matrix. [ABSTRACT FROM AUTHOR]