Biomarkers of endothelial damage in erectile dysfunction based on preclinical studies: a systematic review.

Objective. Blood endothelial progenitor cells (EPCs) and endothelial microparticles (EMPs) have been proposed as markers of endothelial dysfunction. Aim of this study was to evaluate an original immunophenotype of EPCs and EMPs in patients with isolated arterial erectile dysfunction (ED) and late onset hypogonadism (LOH) before and after androgen replacement therapy.Materials and methods. Fifty patients (50–64 years) with ED and LOH were selected. EPC (CD45neg/CD34pos/CD144pos) and EMP (CD45neg/CD34neg/CD144pos) blood concentrations were evaluated by flow cytometry. Thirty patients received androgen replacement therapy (Tostrex® ProStrakan) for 6 months (group A), other 20 patients not received androgen therapy for the contraindications in their clinical history (group B).Results. After 6 months, group B showed IIEF-5 score, peak systolic velocity and acceleration time significantly worse than group A; in addition EPCs and EMPs were significantly higher in group B compared to group A.Conclusions. Patients with isolated arterial ED and LOH not treated with androgen therapy showed worst vascular parameters measured by penile Doppler and higher EPCs and EMPs compared to treated hypogonadal patients, hence, LOH appears to be an additional vascular risk factor, and these markers may be considered as predictors of cavernous artery disease. Finally, androgen therapy improves endothelial dysfunction.

Blood endothelial progenitor cells (EPC) and microparticles (EMP) have been proposed as markers of endothelial dysfunction. The aim of this study was to evaluate a new immunophenotype of EPCs and EMPs in patients with arterial erectile dysfunction (ED) and late-onset hypogonadism (LOH). Fifty patients (58.2 ± 0.7 years) with ED and LOH were enrolled in this study. Their EPC and EMP concentrations were compared with those of 20 patients with arterial ED alone (61.2 ± 1.2 years) and of 20 healthy men (controls; 61.4 ± 1.2 years). EPC (CD45(neg)/CD34(pos)/CD144(pos)) and EMP (CD45(neg)/CD144(pos)/annexin V(pos)) blood concentrations were evaluated by flow cytometry. Patients with ED and LOH or ED alone had significantly higher blood pressure, triglycerides, homeostasis model assessment index of insulin resistance, cavernous artery acceleration time, and intima-media thickness than controls, whereas International Index of Erectile Function score, high-density lipoprotein cholesterol, and cavernous artery peak systolic velocity and resistance index were lower than those of controls. Both EPCs and EMPs were significantly higher in patients with ED and LOH compared with patients with ED alone or controls. Patients with ED alone had EPCs and EMPs significantly higher than controls. In conclusion, patients with ED and LOH showed worse metabolic parameters and cavernous artery parameters, measured by dynamic penile echo color Doppler, and higher EPCs and EMPs compared with patients with ED alone. This suggests that LOH is an additional vascular risk factor and that EPCs and EMPs may be considered predictors of endothelial dysfunction in patients with ED and LOH.

Circulating endothelial cells and endothelial progenitor cells after angioplasty: news from the endothelial rescue squad.

BackgroundAntiphospholipid Syndrome (APS) is an autoimmune disease characterized by recurrent thromboembolic events and pregnancy morbidity associated to the presence of specific serum antibodies directed against membrane phospholipids and proteic co-factors...

Atherosclerosis begins in childhood, progresses silently through a long preclinical stage, and eventually manifests clinically, usually from middle age. Over the last 30 years, it has become clear that the initiation and progression of disease, and its later activation to increase the risk of morbid events, depends on profound dynamic changes in vascular biology.1 The endothelium has emerged as the key regulator of vascular homeostasis, in that it has not merely a barrier function but also acts as an active signal transducer for circulating influences that modify the vessel wall phenotype.2 Alteration in endothelial function precedes the development of morphological atherosclerotic changes and can also contribute to lesion development and later clinical complications.3 Appreciation of the central role of the endothelium throughout the atherosclerotic disease process has led to the development of a range of methods to test different aspects of its function, which include measures of both endothelial injury and repair. These have provided not only novel insights into pathophysiology, but also a clinical opportunity to detect early disease, quantify risk, judge response to interventions designed to prevent progression of early disease, and reduce later adverse events in patients. The present review summarizes current understanding of endothelial biology in health and disease, the strengths and weaknesses of current testing strategies, and their potential applications in clinical research and patient care. Although only a simple monolayer, the healthy endothelium is optimally placed and is able to respond to physical and chemical signals by production of a wide range of factors that regulate vascular tone, cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. The importance of the endothelium was first recognized by its effect on vascular tone. This is achieved by production and release of several vasoactive molecules that relax or constrict the vessel, as …

Endothelial Progenitors and Blood Microparticles: Are They Relevant to Heart Failure With Preserved Ejection Fraction?

Chronic autoimmune diseases are associated with increased risk of cardiovascular death. Endothelial dysfunction represents the first stage of subclinical atherosclerosis and multiple factors contribute to endothelial injury. Among these, an altered balance between endothelial microparticle (EMP) release and endothelial progenitor cell (EPC) generation promotes endothelial dysfunction. The role of EMPs and EPCs in promoting endothelial damage in primary SS (pSS) has never been investigated. Our aim was to evaluate the role of EMPs and EPCs as markers of endothelial damage in pSS and their correlation with disease clinical and immunological features. Circulating EMPs (CD31(+)/CD42(-)), true EPCs (CD34(+)/KDR(+)/CD133(+)) and mature EPCs (CD34(+)/KDR(+)/CD133(-)) were quantified by FACS analysis in 34 pSS patients and 18 age- and sex-matched controls. Correlation between EMP and EPC levels and parameters of disease activity and damage, clinical features and markers of immunological dysfunction was performed. Patients displayed higher EMP numbers with respect to healthy controls [HCs; mean 450 n/μl (S.D. 155) vs 231 (110), P < 0.0001]. EPC and mature EPC levels were higher in patients compared with HCs [mean 226 n/ml (S.D. 181) vs 69 (53), P < 0.001 and 166 (161) vs 36 (32), P < 0.0001, respectively). EMP levels directly correlated with disease duration from symptoms and diagnosis (ρ = 0.5, P < 0.01). Early EPCs inversely correlated with disease duration from symptoms (ρ = -0.5, P < 0.01) and diagnosis (ρ = -0.4, P < 0.05). This is the first demonstration of chronic endothelial fragmentation characterizing pSS. The reparative potentiality of the endothelial layer appears to be preserved in the earliest stages of disease. During the course of the disease, progressive exhaustion of the precursor endothelial pool may be hypothesized, leading to defective vascular layer restoration and endothelial dysfunction.

Mediterranean diet reduces endothelial damage and improves the regenerative capacity of endothelium

IntroductionExcessive sympathoadrenal activation in critical illness contributes directly to organ damage, and high concentrations of catecholamines damage the vascular endothelium. This study investigated associations between potential drivers of sympathoadrenal activation, circulating catecholamines and biomarkers of endothelial damage and outcome in ST segment elevation myocardial infarction (STEMI)-patients, hypothesizing that the catecholamine surge would reflect shock degree and correlate with biomarkers of endothelial damage.MethodsThis was a prospective study of 678 consecutive STEMI-patients admitted to a single high-volume invasive heart centre for primary percutaneous coronary intervention (pPCI) from September 2006 to July 2008. Blood samples were drawn immediately before pPCI. Plasma adrenaline, noradrenaline, syndecan-1 and thrombomodulin were measured retrospectively with complete data in 571 patients (84%). Median follow-up time was 28 (IQR 23 to 34) months. Follow-up was 99.7% complete. Outcomes were all-cause and cardiovascular mortality, re-myocardial infarction and admission due to heart failure.ResultsCirculating noradrenaline and adrenaline correlated weakly but independently with syndecan-1 (rho = 0.15 and rho = 0.13, both P <0.01) and thrombomodulin (rho = 0.11 and rho = 0.17, both P <0.01), biomarkers of glycocalyx and endothelial cell damage, respectively. Considering biomarkers, patients with shock pre-pPCI had higher adrenaline and syndecan-1 and patients admitted to ICU post-pPCI had higher syndecan-1 (all P <0.05), and in the patients with shock (n = 51) catecholamines correlated strongly with thrombomodulin and syndecan-1 (rho = 0.31 to 0.42, all P <0.05). During follow-up, 78 (14%) patients died (37 cardiovascular deaths) and 65 (11%) were admitted with heart failure. By multivariate Cox proportional hazards analyses, one quartile higher plasma adrenaline was weakly but independently associated with both 30-day and long term mortality and heart failure (30-day all-cause mortality hazard ratio (95% CI) 1.39 (1.01 to 1.92), P = 0.046; 30-day heart failure 1.65 (1.17 to 2.34), P = 0.005; and long-term cardiovascular mortality 1.49 (1.08 to 2.04), P = 0.014). Furthermore, one quartile higher syndecan-1 was also weakly but independently associated with long-term all cause mortality (1.26 (1.02 to 1.57), P = 0.034).ConclusionsIn STEMI patients treated with pPCI, catecholamines correlated weakly with biomarkers of endothelial damage, with the strongest correlations and highest adrenaline and syndecan-1 levels in patients with shock. Furthermore, adrenaline and syndecan-1 were weakly but independently associated with mortality and heart failure. Acute myocardial infarction appears to cause significant endothelial cell and glycocalyx injury and a parallel increase in circulating catecholamines.

We recently showed the diagnostic value of a new immunophenotype of blood endothelial progenitor cells (EPC) (CD45(-)/CD34(+)/CD144(+)) and endothelial microparticles (EMP) (CD45(-)/CD144(+)/annexin V(+)) in patients with arterial erectile dysfunction (AED), particularly in patients with associated late-onset hypogonadism and/or metabolic syndrome. In addition, we evaluated the effects of androgen replacement therapy, aerobic physical activity, and tadalafil administration on these markers. The aim of this study was to evaluate the serum concentrations of EPCs and EMPs in a large cohort of patients with AED according to severity of cavernous arterial insufficiency evaluated by penile Doppler. A total of 120 patients (aged 58.0 ± 6.0 years) with AED were enrolled in this study. Patients were classified into 3 groups based on value of peak systolic velocity (PSV). Group A: 37 patients with PSV <25 cm/s (severe arterial insufficiency); group B: 40 patients with PSV between 25 and 29 cm/s (moderate arterial insufficiency); group C: 43 patients with PSV between 30 and 34 cm/s (mild arterial insufficiency). Twenty patients (aged 60.0 ± 3.0 years) with psychogenic erectile dysfunction (PED) represented the control group. EPC and EMP blood concentrations were evaluated by flow cytometry. Patients with AED had significantly higher blood pressure, triglyceride levels, homeostasis model assessment index of insulin resistance, cavernous artery acceleration time, and intima-media thickness than those with PED, whereas International Index of Erectile Function score, high-density lipoprotein cholesterol level, and cavernous artery PSV were lower than those in PED. Both EPC and EMP levels were significantly higher in patients with AED compared with patients with PED. Among 3 groups of patients with AED, there were no significant differences in metabolic parameters examined, but group A showed significantly higher values of cavernous artery acceleration time and intima-media thickness than group B and group C. Finally, group A showed serum concentrations of EPCs and EMPs significantly higher compared with other groups with AED. Patients with AED showed worse metabolic parameters, cavernous artery parameters, and EPC and EMP levels compared with patients with PED. Among patients with AED, those with PSV <25 cm/s showed worse findings of endothelial dysfunction. This suggests that AED is an expression of endothelial damage and that this original immunophenotype of EPCs and EMPs may be considered a predictor of endothelial dysfunction in patients with AED. Finally, this study confirmed the reliability of penile Doppler evaluation integrated with these serum markers of endothelial dysfunction.

BackgroundSubclinical atherosclerosis can be considered a form of systemic involvement in patients with chronic inflammatory joint and connective tissue diseases. Multiple factors, including inflammatory and immune-mediated mechanisms, have been identified...

The balance between lesion and regeneration of the endothelium is critical for the maintenance of vessel integrity. Exposure to cardiovascular risk factors (CRF) alters the regulatory functions of the endothelium that progresses from a quiescent state to activation, apoptosis and death. In the last 10 years, identification of circulating endothelial cells (CEC) and endothelial-derived microparticles (EMP) in the circulation has raised considerable interest as non-invasive markers of vascular dysfunction. Indeed, these endothelial-derived biomarkers were associated with most of the CRFs, were indicative of a poor clinical outcome in atherothrombotic disorders and correlated with established parameters of endothelial dysfunction. CEC and EMP also behave as potential pathogenic vectors able to accelerate endothelial dysfunction and promote disease progression. The endothelial response to injury has been enlarged by the discovery of a powerful physiological repair process based on the recruitment of circulating endothelial progenitor cells (EPC) from the bone marrow. Recent studies indicate that reduction of EPC number and function by CRF plays a critical role in the progression of cardiovascular diseases. This EPC-mediated repair to injury response can be integrated into a clinical endothelial phenotype defining the ‘vascular competence’ of each individual. In the future, provided that standardization of available methodologies could be achieved, multimarker strategies combining CEC, EMP and EPC levels as integrative markers of ‘vascular competence’ may offer new perspectives to assess vascular risk and to monitor treatment efficacy.

To investigate the effect of icariin on endothelial microparticles, endothelial progenitor cells, platelets, and erectile function in spontaneously hypertensive rats. Twelve 8-week-old healthy male Wistar-Kyoto rats and 12 spontaneously hypertensive rats were randomly divided into four following groups: Wistar-Kyoto control group (normal saline 1ml/d given by gavage), Wistar-Kyoto + icariin group (icariin 10mg/kg × d dissolved in 1ml normal saline and given by gavage), spontaneously hypertensive rats control group (normal saline 1ml/d given by gavage), and spontaneously hypertensive rats + icariin group (icariin 10mg/kg × d dissolved in 1ml normal saline and given by gavage). Four weeks later, the maximum intracavernous pressure/mean arterial pressure, platelet count, mean platelet volume, platelet distribution width, endothelial microparticles, endothelial progenitor cells, and vitronectin receptor were measured in each group. Under 3 or 5 V electrical stimulation, the maximum intracavernous pressure/mean arterial pressure in the spontaneously hypertensive rats + icariin group (0.23 ± 0.03, 0.38 ± 0.02) was significantly higher compared to the spontaneously hypertensive rats control group (0.12 ± 0.02, 0.20 ± 0.02) (p<0.05). Platelet count, mean platelet volume, and platelet distribution width in the spontaneously hypertensive rats + icariin group (1103.67 ± 107.70 × 109 /L, 9.08 ± 0.50 fl, 11.87 ± 0.45%) were significantly lower than those in the spontaneously hypertensive rats control group (1298.00 ± 89.54 × 109 /L, 9.72 ± 0.44 fl, 13.03 ± 0.59%) (all p<0.05). Endothelial microparticles, endothelial progenitor cells, and vitronectin receptor in the spontaneously hypertensive rats + icariin group (1.01 ± 0.28%, 1.53 ± 0.65%, 2.13 ± 0.53%) were significantly lower than those in the spontaneously hypertensive rats control group (1.58 ± 0.19%, 2.71 ± 0.64%, 3.76 ± 0.52%) (all p<0.05). Moreover, maximum intracavernous pressure/mean arterial pressure was strongly negatively correlated with platelet distribution width and vitronectin receptor (r>0.7), and maximum intracavernous pressure/mean arterial pressure was moderately negatively correlated with mean platelet volume, endothelial microparticles, and endothelial progenitor cells (0.5<r<0.7). Icariin may improve erectile function in spontaneously hypertensive rats by reducing the content of endothelial microparticles in blood and inhibiting the activation of the platelets. Endothelial microparticles, endothelial progenitor cells, and platelet activation-related (mean platelet volume, platelet distribution width, and vitronectin receptor) can be used as indicators for icariin to improve erectile function in spontaneously hypertensive rats.

Endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are markers of endothelial injury and repair. We compared the effects of pioglitazone versus metformin on the circulating numbers of EMPs and EPCs in patients with newly diagnosed type 2 diabetes. This was a randomized, double-blind, comparator-controlled, 24-week single-centre trial conducted in a Teaching Hospital in Naples, Italy. One hundred and ten people with newly diagnosed type 2 diabetes who were never treated with antihyperglycaemic drugs and had haemoglobin A1c (HbA1c) levels between 7 and 10% were given pioglitazone hydrochloride (15-45 mg/day) (n = 55) or metformin (1000-2000 mg/day) (n = 55) as an active comparator. Absolute change from baseline to final visit in circulating EMPs and EPCs and their ratio were the main outcomes. Baseline characteristics did not differ between the study groups. The decrease in circulating EMPs CD31+ [intergroup difference, -32 counts/µl (95% CI -51 to -9)] and the increase in EPCs CD34+/KDR+ [intergroup difference, 33 cells/10(6) events (95% CI 13 to 55)] were greater with pioglitazone versus metformin. EMPs/EPCs ratio was reduced with pioglitazone and unchanged with metformin [difference, -1.5 (95% CI -2.6 to -0.5), p < 0.001]. Participants assigned to pioglitazone gained more weight and experienced greater improvements in some coronary risk measures [high-density lipoprotein (HDL)-cholesterol, triglycerides, adiponectin and C-reactive protein (CRP)] than did those assigned to metformin. Compared with metformin, pioglitazone treatment improved the imbalance between endothelial damage and repair capacity and led to more favourable changes in coronary risk factors in patients with newly diagnosed type 2 diabetes.

Circulating endothelial microparticles are elevated in bicuspid aortic valve disease and related to aortic dilation