Nicolás Renna

Pathophysiology of vascular remodeling in hypertension

Vascular remodeling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Glagovs contribution. We then move to some basic concepts on the biomechanics of blood vessels and explain the definitions proposed by Mulvany for specific forms of remodeling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodeled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodeling is described, again with emphasis on human data. Some details are given on the three mechanisms to date which point to remodeling resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodeling in the pathogenesis of endorgan damage and in the perpetuation of hypertension.

Aqueous garlic extracts prevent oxidative stress and vascular remodeling in an experimental model of metabolic syndrome.

The organosulfur profile and the effect on oxidative stress and vascular remodeling in fructose-fed rats (FFR) were evaluated in Fuego INTA and Morado INTA garlic cultivars. Wistar rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. During the last 6 weeks of a 12 week period of the corresponding diet, a subgroup of control and FFR received an aqueous extract of Fuego INTA and Morado INTA. Fuego INTA showed higher levels of total thiosulfinates, allicin, and pungency than Morado INTA. FFR showed an increase of systolic blood pressure, aortic NAD(P)H oxidase activity, plasma thiobarbituric acid reactive substances, and vascular remodeling that was significantly reduced after both garlic administrations. The beneficial effect was slightly higher when Fuego INTA was administered. Both aqueous garlic extracts prevent oxidative stress and vascular remodeling in rats with metabolic syndrome, suggesting the existence of slight differences among cultivars.

Effect of chronic aspirin administration on an experimental model of metabolic syndrome.

1 The aim of the present study was to examine the effect of chronic administration of aspirin on metabolic and cardiovascular parameters in fructose‐fed rats (FFR), an experimental model of metabolic syndrome. 2 Chronic treatment of FFR with aspirin (10 mg/kg per day for 6 weeks) partially reversed the increment in systolic blood pressure. In addition, chronic aspirin treatment normalized relative heart weight and vascular remodelling of renal and carotid arteries, measured as lumen diameter : medial thickness ratio. 3 Furthermore, chronic aspirin administration completely reversed glucose intolerance and decreased the oxidative status that characterizes the FFR model, as indicated by decreased plasma levels of thiobarbituric acid‐reactive substances and aortic NAD(P)H oxidase activity. 4 Prevention of oxidative stress and vascular remodelling in FFR may contribute to the protective actions attributed to aspirin in the treatment of metabolic syndrome.

Role of Renin-Angiotensin System and Oxidative Stress on Vascular Inflammation in Insulin Resistence Model

(1) This study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inflammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10−3 mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3) Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4) The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury.

Effect of Red Wine on Adipocytokine Expression and Vascular Alterations in Fructose-Fed Rats

BACKGROUND Imbalance in adipocytokines secretion is related to the development of metabolic syndrome (MS). In addition, moderate consumption of red wine (RW) decreases the risk of cardiovascular disease. The aim of this study was to evaluate the effects of moderate consumption of RW or ethanol (E) on adiponectin and resistin expression, and vascular alterations in fructose-fed rats (FFRs) as an experimental model of MS. METHODS Thirty-day-old male Wistar rats were assigned to control (C), F (10% fructose in drinking water), F+E (4.5 ml/kg), and F+RW (35 ml/kg of Malbec RW containing 4.5 ml/kg E). E and RW were administered during the last 4 weeks of a 10-week period. RESULTS RW administration to F rats was able to significantly decrease insulin resistance, mesenteric adipose tissue weight, and systolic blood pressure (SBP) compared to F group. F+E only reduced the SBP (P < 0.05 vs. F). F+RW also reduced aortic NAD(P)H-oxidase activity, NAD(P)H subunits Nox4 expression in mesenteric tissue, plasma thiobarbituric acid reactive substances (TBARS), and recovered plasma total antioxidant activity (TAA) compared to F and F+E groups (P < 0.05). Adiponectin expression decreased, whereas resistin, vascular cell adhesion molecules-1 (VCAM-1), and nuclear factor-κB (NF-κB) expression and vascular remodeling in mesenteric arteries were higher in F than in C group (P < 0.05). Only RW was able to partially reverse the aforementioned alterations. CONCLUSION In this study, Malbec RW, but not alcohol alone, improved the balance of adipocytokines and attenuated the oxidative stress and vascular inflammation in a model of MS, suggesting that nonalcohol components of RW are responsible for the beneficial effects.

Role of Cox-2 in Vascular Inflammation: An Experimental Model of Metabolic Syndrome

The objective of this work was to demonstrate the role of COX-2 enzyme at the vascular in experimental model of metabolic syndrome. SHR male WKY rats were employed; they were distributed in 8 groups (n = 8 each): control (W); W + L: WKY rats receiving 20 mg/kg of lumiracoxib by intraesophageal administration; SHR; SHR + L: SHR + 20 mg/kg of lumiracoxib by intraesophageal administration; Fructose-Fed Rats (FFR): WKY rats receiving 10% (w/v) fructose solution in drinking water during all 12 weeks; FFR + L: FFR + 20 mg/kg of lumiracoxib by intraesophageal administration; Fructose-Fed Hypertensive Rats (FFHR): SHR receiving 10% (w/v) fructose solution in drinking water during all 12 weeks; and FFHR + L: FFHR + 20 mg/kg of lumiracoxib by intraesophageal administration. Metabolic variables, blood pressure, morphometric variables, and oxidative stress variables were evaluated; also MMP-2 and MMP-9 (collagenases), VCAM-1, and NF-κB by Westernblot or IFI were evaluated. FFHR presented all variables of metabolic syndrome; there was also an increase in oxidative stress variables; vascular remodeling and left ventricular hypertrophy were evidenced along with a significant increase in the expression of the mentioned proinflammatory molecules and increased activity and expression of collagenase. Lumiracoxib was able to reverse vascular remodeling changes and inflammation, demonstrating the involvement of COX-2 in the pathophysiology of vascular remodeling in this experimental model.

Effects of Dipeptidyl-Peptidase 4 Inhibitor about Vascular Inflammation in a Metabolic Syndrome Model

Background In this study, we used vidagliptin(V) to examine the role of the DDP-IV, incretin system component, in the activation of different molecular inflammatory cytokines, NF-kB and VCAM-1 to generate a microenvironment that supports cardiovascular remodeling. Methods Male WKY and SHR were separated into five groups: Control, FFR: WKY rats receiving a 10% (w/v) fructose solution during all 12 weeks, SHR, FFHR: SHR receiving a 10% (w/v) fructose solution during all 12 weeks and FFHR+V: (5 mg/kg per day for 6 weeks) (n = 8 each group). Metabolic variables and systolic blood pressure were measured. The TBRAS, eNOS activity, and NAD(P)H oxidase activity were estimated to evaluate oxidative stress. Cardiac and vascular remodeling were evaluated. To assess the cytokine, NF-kB and VCAM-1 immunostaining techniques were used. Results The FFHR experimental model presents metabolic syndrome criteria, vascular and cardiac remodeling, vascular inflammation due to increased expression of NF-kB, VCAM-1, and pro-atherogenic cytokines. Chronic treatment with V was able to reverse total or partiality of variables studied. Conclusions Data demonstrated an important effect of DDP-IV in reducing vascular inflammation, accompanied by a favorable reduction in metabolic and structural parameters.

Apoptosis of endothelial progenitor cells in a metabolic syndrome experimental model

Aim: This study tests the hypothesis postulating that metabolic syndrome induced by chronic administration of fructose to spontaneously hypertensive rats (FFHR) generates impairment in vascular repair by endothelial progenitor cells (EPC). Materials and Methods: To characterize the vascular adverse environment present in this experimental model we measured: NAD(P)H oxidase activity, eNOS activity, presence of apoptosis in the arterial wall, all these parameters were most affected in the FFHR group. Also, we found decreased level and proliferative capacity of EPC measured by flow cytometry and colonies forming units assay in cultured cells, respectively, in both groups treated with fructose; FFHR (SHR fructose fed rats) and FFR (WKY fructose fed rats) compared with their controls; SHR and WKY. Results: The fructose-fed groups FFR and SHR also showed an incremented number of apoptotic (annexinV+/7AADdim) EPC measured by flow cytometry that returns to almost normal values after eliminating fructose administration. Conclusion: Our findings suggest that increased apoptosis levels of EPC generated in this experimental model could bein part the underlying cause for the impaired vascular repair by in EPC.

Oxidative Stress, Vascular Remodeling, and Vascular Inflammation in Hypertension

Hypertension is a major public health problem worldwide, affecting over 50 million individuals in the United States alone. The modern history of hypertension begins with the understanding of the cardiovascular system with the work of the physician William Harvey (1578–1657), who described the circulation of blood in his book De Motu Cordis. The English clergyman Stephen Hales made the first published measurement of blood pressure in 1733. Frederick Akbar Mahomed (1849–1884) made the first report of elevated blood pressure in a person without evidence of kidney disease. However, hypertension as a clinical entity came into being in 1896 with the invention of the cuff-based sphygmomanometer by Scipione Riva-Rocci. This apparatus has allowed the measurement of the blood pressure into the clinic. In 1905, Nikolai Korotkoff improved the technique by describing the Korotkoff sounds that are heard when the artery is auscultated with a stethoscope while the sphygmomanometer cuff is deflated. The concept of essential hypertension (“hypertonic essential”) was introduced in 1925 by the physiologist Otto Frank to describe elevated blood pressure for which no cause could be found. Over the several decades, increasing evidence accumulated from actuarial reports and longitudinal studies, such as the Framingham Heart Study. In the actuality, the term “inflammation” is used in the context of cardiovascular disease as a catchall referring to nonspecific phenomena, such as elevation of C-reactive protein. Most clinicians and investigators find this vague and difficult to understand. In this issue, we will attempt to address some of these puzzling questions. In this way, several authors write on oxidative stress in the pathophysiology of target organ damage. G. Csanyi and P. J. Pagano postulated that peptides mimicking the Nox4 B-loop and regions C-terminus on inhibit Nox4 activity and their findings suggest that Nox4 exists in a tightly assembled and active conformation which, unlike other Noxes, cannot be disrupted by conventional means. R. O. Maranon et al. demonstrated, in nonischemic 5/6 nephrectomized rat (NefR), a model of chronic kidney disease, that tempol improves NO-contents and basal tone, without decrease MAP, indicating that oxidative stress could be implicated early and independently to hypertension, in the vascular alterations. B. P. Campagnaro et al. proposed that the non-hemodynamic effects of angiotensin II are important for the damage observed in the two-kidney, one-clip (2K1C) renovascular hypertension model and demonstrated that 2K1C hypertensive mice have an elevated lymphocyte count, while undifferentiated bone marrow mononuclear cells counts were diminished. N. Arias et al. describe mechanisms associated with inflammation and oxidative stress in the brain. N. Arias et al., in their study, examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). S.-L. Chan and G. L. Baumbach examined the role of genetic deficiency of NAD(P)H-oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension and concluded that hypertension-induced superoxide production derived from Nox2-containing NADPH oxidase promotes hypertrophy and causes endothelial dysfunction in cerebral arterioles, possibly involving interaction with nitric oxide. On the other hand, J. Alvarez-Camacho et al. describe the pathophysiologic link between the metabolic syndrome, obesity, hypertension, and adipokines at experimental and clinical level. J. Alvarez-Camacho et al. addresse topics related to modern aspects in the pathophysiology of hypertension such as the role of inflammation, environment, epigenetics, and adiponectin in hypertension, and Y. Mendizabal et al. discuss the central role of hypertension and vascular inflammation in metabolic syndrome and the role of sympathetic tone. Subsequently, they examine the link between endothelial dysfunction and insulin resistance. Finally, animal models used in the study of vascular function of metabolic syndrome are reviewed, in particular, the Zucker fatty rat and the spontaneously hypertensive obese rat (SHROB). N. F. Renna et al. conducted a review of the mechanisms involved in the physiopathological vascular changes, adaptive and maladaptive, called vascular remodeling and the involvement of inflammatory mechanisms. Finally, D. M. Babbitt et al. performed their analysis on a clinical protocol that demonstrated that aerobic exercise training might be a viable, nonpharmacological method to improve inflammation status and endothelial function and thereby contribute to risk reduction for cardiovascular disease in African Americans. In conclusion, the observed elevation in inflammatory parameters in subjects who subsequently go on to develop hypertension is particularly relevant and creates options for potential primary prevention strategies. A number of therapeutic agents have been identified which are able to influence this inflammatory process and positively influence cardiovascular outcomes. Nicolas Federico Renna

Vascular Repair and Remodeling: A Review

Vascular remodeling is alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. In this review, physiopathology of vascular remodeling is discussed, and the impact of antihypertensive drug treatment on remodeling is described, emphasizing on human data, fundamentally as an independent predictor of cardiovascular risk in hypertensive patients. Then we discussed a vascular repair by endothelial progenitor cells (EPCs) that play important roles in the regeneration of the vascular endothelial cells (ECs). The normal arterial vessel wall is mostly composed of ECs, vascular smooth muscle cells (VSMCs), and macrophages. Endothelial impairment is a major contributor to atherosclerosis and restenosis after percutaneous coronary intervention (PCI). Reendothelialization can effectively inhibit VSMC migration and proliferation and decrease neointimal thickening.