Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications

Aging is the primary risk factor underlying hypertension and incident cardiovascular disease. With aging, the vasculature undergoes structural and functional changes characterized by endothelial dysfunction, wall thickening, reduced distensibility, and arterial stiffening. Vascular stiffness results from fibrosis and extracellular matrix (ECM) remodelling, processes that are associated with aging and are amplified by hypertension. Some recently characterized molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor-β1/SMAD signalling, upregulation of galectin-3, and activation of proinflammatory and profibrotic signalling pathways. These events can be induced by vasoactive agents, such as angiotensin II, endothelin-1, and aldosterone, which are increased in the vasculature during aging and hypertension. Complex interplay between the “aging process” and prohypertensive factors results in accelerated vascular remodelling and fibrosis and increased arterial stiffness, which is typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of “early” or “premature” vascular aging is now often used to describe hypertension-associated vascular disease. We review the vascular phenotype in aging and hypertension, focusing on arterial stiffness and vascular remodelling. We also highlight the clinical implications of these processes and discuss some novel molecular mechanisms of fibrosis and ECM reorganization

Progenitor cells, bone marrow–derived fibrocytes and endothelial-to-mesenchymal transition: new players in vascular fibrosis

No abstract available

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function

Hydrogen PEMFC stack performance analysis : a data-driven approach

For low power fuel cells, it is paramount that management of reactants, water and heat, be realized in a passive fashion in order to minimize parasitic losses. Effective fuel, oxygen supply and water management for reliable performance are also greatly affected by cell geometry and materials. Fuel cells are complex systems to optimize on a mere experimental basis. As an aid to this goal, data-driven analysis techniques, requiring no mathematical model to be fixed a priori, are gaining a reputation in other fields of work, where a phenomenological modeling approach might be intractable. This work presents a characterization study of a 12W PEMFC series stack by means of a new data-driven technique, M-NMF. The stack was developed for low temperature operation, uses own designed flow field plates, integrated in a series configuration, and is operated for 12 combinations of hydrogen/air flowrate ratios, generating as many polarization curves. M-NMF is applied, in combination with an alternating least squares algorithm, to the analysis of the overvoltage data matrix derived from the original experimental polarization data. From this analysis, it is possible to group and differentiate data according to similar overvoltage patterns and gain insight into their relative contribution to fuel cell performance immunization

Novel data-driven methodologies for parameter estimation and interpretation of fuel cells performance

Fuel cell based power generation systems are expected to become more widespread in the near future. Stationary fuel cells may be used as an uninterruptible or back-up power supply, or to supply micro-grids. In particular, proton exchange membrane fuel cells (PEMFC) are an attractive technology due to its high energy density, rigid and simple structure, low operating temperature and fast start-up characteristics. The power quality assessment of fuel cells as a viable power sources requires a good understanding of the fuel cell performance characteristics. This paper presents two novel data-driven methodologies for the identification of the main steady state (polarization curve) and the dynamic (impedance response) characteristics for fuel-cells allowing the development of rapid, accurate and empirical models based on the experimental data. M-NMF is a modified non-negative matrix factorization technique developed for the analysis of polarization curve data that allows to identify the three main contributions for the fuel-cell power degradation, while for impedance spectroscopy data, this paper proposes the use of fractional order transfer functions (FC-FOTC) to describe the main dynamic modes present in the fuel-cell. A brief description of these two approaches is presented, together with the analysis of a real experimental dataset obtained from a 12W open cathode PEMFC stack to illustrate their potential and scope. While the former is instrumental for the deconvolution of the fuel cell polarization curves into its major components, the latter enables the estimation of the parameters related to the inherent transport and kinetic phenomena, thus opening the way, in both cases, for the interpretation of the effect of the operating conditions on the relative dominance and magnitude of these components and phenomena

Electrochemical impedance spectroscopy modeling using the dis-tribution of relaxation times and error analysis for fuel cells

This paper proposes a new approach to determine the distribution of relaxation times (DRT) directly from the electro-chemical impedance spectroscopy (EIS) data, i.e. without the use of an equivalent electrical circuit model. The method uses a generalized fractional-order Laguerre basis to represent EIS where both the parameters of the basis and their co-efficients are estimated by solving a nonconvex minimization problem. Furthermore, the DRT confidence region is de-termined to assess the accuracy and precision of the DRT estimate. The approach is applied to analyze the dominant dynamic properties of an open-cathode hydrogen fuel-cell under different current and air-flow conditions. Results showed that the estimated DRT closely reconstructs EIS data even when there is a higher variance at smaller relaxation times

Vascular smooth muscle contraction in hypertension

Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex interacting systems such as the renin angiotensin aldosterone system (RAAS), sympathetic nervous system, immune activation and oxidative stress, which influence vascular smooth muscle function. Vascular smooth muscle cells are highly plastic and in pathological conditions undergo phenotypic changes from a contractile to a proliferative state. Vascular smooth muscle contraction is triggered by an increase in intracellular free calcium concentration ([Ca2+]i), promoting actin-myosin cross-bridge formation. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase (ROCK), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling, reactive oxygen species and reorganization of the actin cytoskeleton. Activation of immune/inflammatory pathways and noncoding RNAs are also emerging as important regulators of vascular function. Vascular smooth muscle cell [Ca2+]i, not only determines the contractile state but also influences activity of many calcium-dependent transcription factors and proteins thereby impacting the cellular phenotype and function. Perturbations in vascular smooth muscle cell signaling and altered function influence vascular reactivity and tone, important determinants of vascular resistance and blood pressure. Here we discuss mechanisms regulating vascular reactivity and contraction in physiological and pathophysiological conditions and highlight some new advances in the field, focusing specifically on hypertension

Vascular dysfunction and fibrosis in stroke-prone spontaneously hypertensive rats: the aldosterone-mineralocorticoid receptor-Nox1 Axis

Aims: We questioned whether aldosterone and oxidative stress play a role in vascular damage in severe hypertension and investigated the role of Nox1 in this process. Materials and methods: We studied mesenteric arteries, aortas and vascular smooth muscle cells (VSMC) from WKY and SHRSP rats. Vascular effects of eplerenone or canrenoic acid (CA) (mineralocorticoid receptor (MR) blockers), ML171 (Nox1 inhibitor) and EHT1864 (Rac1/2 inhibitor) were assessed. Nox1-knockout mice were also studied. Vessels and VSMCs were probed for Noxs, reactive oxygen species (ROS) and pro-fibrotic/inflammatory signaling. Key findings: Blood pressure and plasma levels of aldosterone and galectin-3 were increased in SHRSP versus WKY. Acetylcholine-induced vasorelaxation was decreased (61% vs 115%) and phenylephrine-induced contraction increased in SHRSP versus WKY (Emax 132.8% vs 96.9%, p < 0.05). Eplerenone, ML171 and EHT1864 attenuated hypercontractility in SHRSP. Vascular expression of collagen, fibronectin, TGFβ, MCP-1, RANTES, MMP2, MMP9 and p66Shc was increased in SHRSP versus WKY. These changes were associated with increased ROS generation, 3-nitrotyrosine expression and Nox1 upregulation. Activation of vascular p66Shc and increased expression of Nox1 and collagen I were prevented by CA in SHRSP. Nox1 expression was increased in aldosterone-stimulated WKY VSMCs, an effect that was amplified in SHRSP VSMCs (5.2vs9.9 fold-increase). ML171 prevented aldosterone-induced VSMC Nox1-ROS production. Aldosterone increased vascular expression of fibronectin and PAI-1 in wild-type mice but not in Nox1-knockout mice. Significance: Our findings suggest that aldosterone, which is increased in SHRSP, induces vascular damage through MR-Nox1-p66Shc-mediated processes that modulate pro-fibrotic and pro-inflammatory signaling pathways

Assessing cell polarity reversal degradation phenomena in PEM Fuel Cells by electrochemical impedance spectroscopy

The mechanisms of fuel cell degradation are multiple and not well understood. Irreversible changes in the kinetic and/or transport properties of the cell are fostered by thermal, chemical and mechanical issues which constrain stability, power and fuel cell lifetime. Within the in-situ diagnostics methods and tools available, in-situ electrochemical impedance spectroscopy (EIS) is within the most promising to better understand and categorize changes during fuel cell ageing. In this work, the degradation phenomena caused by cell polarity reversal due to fuel starvation of an open cathode 16 MEA (membrane-electrode assembly) –low power PEM fuel cell (15 W nominal power) is reported using EIS as a base technique. A frequency response analyzer from Solartron Model 1250 was used connected to an electrochemical interface also from Solartron, Model 1286. The range of covered frequencies spans from 37000 Hz to 0.01Hz. Hydrogen is supplied from a metallic hydride small reactor with a capacity of 50 NL H2 at a pressure of 0.2 bar. Measuring the potential of individual cells, while the fuel cell is on load, was found instrumental in assessing the “state of health” of cells at fixed current. Location of affected cells, those farthest away from hydrogen entry in the stack, was revealed by the very low or even negative potential values. EIS spectra were taken at selected break-in periods during fuel cell functioning. The analysis of impedance data is made using two different approaches: using an a priori equivalent circuit describing the transfer function of the system in question -equivalent circuit elements were evaluated by a complex non-linear least square (CNLS) fitting algorithm, and by calculating and analyzing the corresponding distribution of relaxation times (DRT) -avoiding the ambiguity of the a priori equivalent circuit and the need for provision of the initial fitting parameters. A resistance and two RQ elements connected in series are identified as describing the impedance response of the cell during normal functioning. A constant phase element (CPE) was chosen to describe the impedance observed behavior. The quality of the fit was evaluated by analysis of the residuals between the fit result and the measured data at every single point. Consistency and quality of the impedance data were established by Kramers-Kronning validation. With continuous operation, using a reduced hydrogen flow, an inversion of polarity was observed in the 16th cell of the stack, evident in the potential measurement of individual cells as a result of insufficient hydrogen to reach the last cells. EIS data analyses suggest that water electrolysis happens at the anode judging by the appearance of an intermediate semicircle associated to a marked change in resistance and capacitance values. The presence of an inductive loop at low frequencies is now evident, which cannot be explained by the relaxation of reaction intermediates involved in the oxygen reduction reaction [1]. It is to be noticed that when the incursion into the negative potential values is not too marked the phenomenon is partially reversible, so it is suggested that the relaxation is due to intermediates in the water electrolysis process. The anode potential rose to levels compatible with the oxidation of water. Once the phenomenon is made irreversible and when water is no longer available, oxidation of the carbon support is favored accelerating catalyst sintering. Ex-situ MEA cross section analysis, under a scanning electron microscope, confirmed it. Electrode thickness reduction and delamination of catalyst layers were observed as a result of reactions taking place during hydrogen starvation. Carbon corrosion and membrane degradation are analyzed, according to evidence by SEM

Relaxation time distribution analysis of a polymer electrolyte fuel cell stack from its impedance response

Electrochemical impedance spectroscopy (EIS) is an analysis technique that is commonly used as a base diagnostics technique for the in-situ analysis of the kinetic and transport properties of proton exchange membrane (PEM) fuel cells. This work proposes to use the distribution of relaxation times (DRT) as a complementary analysis technique for the interpretation of EIS data. For this purpose, the DRT is deduced for a modified Randles electric circuit composed of a constant phase element (CPE) connected in parallel with a resistance in series with a finite diffusion Warburg element. The experimental EIS data collected from an eight cell PEMFC with an open-air cathode was modeled through the use of two modified Randles circuit representing the fuel-cell electrodes. The analysis of the DRT allows to identify further characteristics of the individual processes that occur at both electrodes, while also being instrumental in detecting the effect on the fuel cell performance of some operating conditions, namely hydrogen flow-rate and current