Progressive Vascular Dysfunction Research Articles

ET‐1 Receptor Function in Women with Advancing Reproductive Age

Endothelin‐1 (ET‐1) contributes to endothelial dysfunction, a primary driver of hypertension and cardiovascular disease. Our lab has previously shown that the ETB receptor mediates vasodilation in premenopausal women (PRE), but this effect is lost in postmenopausal women (POST). Noticeable declines in endothelial function are evident early in the menopausal transition, but the function of the ETB receptor in perimenopausal women (PERI) is unclear.PURPOSEThe purpose of this study was to test the hypothesis that ETB‐mediated vasodilation progressively declines with advancing reproductive age in women.METHODSWe used the STRAW+10 staging criteria to classify women as PRE (n=12, 26±2 yrs, 23±1 kg/m2, 83±2 mmHg), PERI (n=9, 50±1 yrs, 24±1 kg/m2, 84±3 mmHg), or POST (n=11, 56±1 yrs, 24±1 kg/m2, 87±2 mmHg). Cutaneous vasodilatory responses to local heating were measured using laser doppler flowmetry during microdialysis perfusions of lactated Ringer’s (Control), ETB receptor blockade (BQ‐788, 300nM), and ETA receptor blockade (BQ‐123, 500nM). Cutaneous vascular conductance (CVC) was calculated during the plateau phase of local heating (42°C), and normalized to maximal vasodilation achieved by perfusion of sodium nitroprusside (28mM) and heating to 43°C.RESULTSPRE showed the greatest cutaneous vasodilation in response to local heating (PRE: 93±2; PERI: 84±2; POST: 88±2 %CVC max, P<0.05 vs PERI and POST). There was a trend for increased vasodilatory responses to ETB receptor blockade with advancing reproductive age (PRE: 85±3; PERI: 91±2; POST: 92±3 %CVC max, P=0.13). However, there were no differences in vasodilatory responses during ETA receptor blockade (PRE: 90±2; PERI: 91±3; POST: 92±3 %CVC max, P=0.84). Finally, brachial artery flow‐mediated dilation tended to decline (PRE: 7±1; PERI: 6±1; POST: 5±1 %Δ, P=0.09) while pulse wave velocity increased with advancing reproductive age (PRE: 6±0; PERI: 7±0; POST: 7±0 m/s, P<0.05 vs PERI and POST).CONCLUSIONSThese preliminary data suggest that adverse changes in vascular function, and potentially ETB receptor function, are evident early in PERI. Therefore, future research examining the role of the ET‐1 pathway in progressive vascular dysfunction throughout the menopausal transition is warranted.Support or Funding InformationNIH R01 HL 146558, P20 GM 113125

Management of cirrhotic ascites.

The most common complication to chronic liver failure is ascites. The formation of ascites in the cirrhotic patient is caused by a complex chain of pathophysiological events involving portal hypertension and progressive vascular dysfunction. Since ascites formation represents a hallmark in the natural history of chronic liver failure it predicts a poor outcome with a 50% mortality rate within 3 years. Patients with ascites are at high risk of developing complications such as spontaneous bacterial peritonitis, hyponatremia and progressive renal impairment. Adequate management of cirrhotic ascites and its complications betters quality of life and increases survival. This paper summarizes the pathophysiology behind cirrhotic ascites and the diagnostic approaches, as well as outlining the current treatment options. Despite improved medical treatment of ascites, liver transplantation remains the ultimate treatment and early referral of the patient to a highly specialized hepatology unit should always be considered.

Childhood obesity, arterial stiffness, and prevalence and treatment of hypertension.

Childhood obesity is associated with progressive vascular dysfunction as manifest by arterial stiffness and elevated blood pressure with associated subsequent morbidity and mortality because of early cardiovascular events including myocardial infarction and stroke in adulthood. Consequently, the recent dramatic increases in childhood obesity around the world present a hitherto unforeseen public health concern. While coordinated primary prevention efforts remain an ongoing important focus of action, identification and treatment of modifiable cardiovascular risk factors in pediatric patients is necessary given the existing burden of disease and future health consequences. Lifestyle interventions remain a cornerstone of our therapeutic approach, however, medical therapy is needed in some cases and should not be underutilized based on patient age. Herein, we discuss the relationship between childhood obesity and hypertension with a key emphasis on the evolution of adaptive and maladaptive vascular changes in the genesis of overt cardiovascular disease.

English

With progressive vascular dysfunction, the endothelial cells mediate increased vessel tone by the synthesis and release of the vasoconstrictor substances primarily endothelin and endothelium-derived constricting factor(s), and by reduced elaboration of vasodilator products primarily nitric oxide. With this background, our study sought correlation of altered lipid profile; a cause of progressive vascular dysfunction, to the relative derangement of the two contrasting vascular biomarkers with respect to anthropometry in apparently healthy individuals. This was a case-control pilot study comprising of 30 overweight/obese healthy subjects (BMI >= 25 kg/m2 and/or WHR (female>0.85; male>1) and 30 non-obese healthy subjects (BMI< 25 kg/m2 and/or WHR (female<0.85; male<1) excluding all subjects with secondary cause of abnormal blood flow. Reactive hyperemia (RH) for indirect evaluation of nitric oxide levels was measured by impedance plethysmography (NICOMON, Larsen & Toubro) in the subject's forearm along with fasting plasma glucose, serum lipids and serum endothelin-1. A significant difference in blood flow index (BFI) at 1 min post-occlusion time (mean ± % SD) {control 1.81 ± 0.42 vs. study 1.60 ± 0.38} (P=0.041) was detected but RH, plasma glucose, lipid profile and serum endothelin were comparable in both the groups with lipid profile derangement present in either group, though not significant. So the two groups were clubbed to seek further association. Out of the two contrasting biomarkers, endothelin-1 and nitric oxide, only latter was significantly altered (raised) in subjects with deranged serum VLDL (P=0.026) and serum triglyceride (P=0.044). Therefore we concluded that altered lipid profile irrespective of measured anthropometric variables, affects the release of nitric oxide and it's like, before any detectable change in serum endothelin-1 levels. This in turn suggested the use of the former to predict the 'subclinical prelude' to 'manifest' metabolic disorder in such apparently healthy subjects and thus ensuring timely premorbid level care.

P50: Cocoa flavanols reverse age-related vascular dysfunction

Background Aging is associated with progressive vascular dysfunction. Cocoa flavanols were shown to improve endothelial vasodilator function and decrease blood pressure.Objectives: The aim of the study was to investigate the effect of a flavanol intervention on circulatory function in healthy elderly subjects. Methods We recruited 22 young ( Results Flavanols “acutely” increase FMD at 1 h after ingestion in both young (6.1 ± 0.7% vs. 7.4 ± 0.8%, p Conclusion Cocoa flavanols improve endothelial function in conduit arteries, conductance of resistance arteries and cutaneous microcirculation. They selectively reverse age-related increases in systolic blood pressure and vascular stiffness. These findings highlight the potential of flavanols to counteract vascular aging. Disclosure Nothing to disclose.

Nanoparticles as magnetic resonance imaging contrast agents for vascular and cardiac diseases

Advances in nanoparticle contrast agents for molecular imaging have made magnetic resonance imaging a promising modality for noninvasive visualization and assessment of vascular and cardiac disease processes. This review provides a description of the various nanoparticles exploited for imaging cardiovascular targets. Nanoparticle probes detecting inflammation, apoptosis, extracellular matrix, and angiogenesis may provide tools for assessing the risk of progressive vascular dysfunction and heart failure. The utility of nanoparticles as multimodal probes and/or theranostic agents has also been investigated. Although clinical application of these nanoparticles is largely unexplored, the potential for enhancing disease diagnosis and treatment is considerable.

Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator

Stroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib, a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis, inflammatory responses, and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to 6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-kappaB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-kappaB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.

Advanced Glycation End Products Induce Blood–Retinal Barrier Dysfunction in Normoglycemic Rats

Advanced glycation end products (AGEs) have been implicated in the progressive vascular dysfunction which occurs during diabetic retinopathy. In the current study we have examined the role of these adducts in blood–retinal barrier (BRB) breakdown and investigated expression of the vasopermeabilizing agent vascular endothelial growth factor (VEGF) in the retina. When normoglycemic rats were injected with AGE-modified albumin daily for up to 10 days there was widespread leakage of FITC-dextran and serum albumin from the retinal vasculature when compared to control animals treated with nonmodified albumin. Ultrastructural examination of the vasculature revealed areas of attenuation of the retinal vascular endothelium and increased vesicular organelles only in the AGE-exposed rats. Quantitative RT-PCR and in situ hybridization demonstrated a significant increase in retinal VEGF mRNA expression (P < 0.05). These results suggest that AGEs can initiate BRB dysfunction in nondiabetic rats and a concomitant increase in retinal VEGF expression. These findings may have implications for the role of AGEs in the pathogenesis of diabetic retinopathy.

Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion.

There are several clinical situations in which large epicardial coronary arteries are deprived of blood flow, such as occurs when an obstructing thrombus or embolus lodges within a vessel or during coronary dissection. There is little information concerning the effect of flow deprivation on large epicardial coronary arteries. We studied a model in which a segment of a large epicardial coronary artery was deprived of blood flow using both proximal and distal clamps for 3 hours followed by reperfusion. On examination by light microscopy of cross sections of the arteries, 19 +/- 6 neutrophils were present in the intima of ischemic/reperfused vessels, whereas only a mean of 4 +/- 3 (SEM) were present in the intima of nonischemic vessels (p less than 0.02). On average, there were 17 +/- 9 neutrophils just under the elastic lamina in ischemic/reperfused vessels versus none in the nonischemic vessels (p less than 0.05); there were 16 +/- 10 neutrophils present within the media of ischemic/reperfused vessels, and none (p less than 0.05) in the nonischemic vessels. Electron microscopic analysis revealed that neutrophils in the ischemic/reperfused vessels were often "sandwiched" between the endothelial cells and the elastic lamina. Ultrastructural abnormalities within the myocardium also revealed damage to the microvasculature, including the presence of neutrophils within the vessels and erythrocyte stasis. To rule out the possibility that findings in the large epicardial arteries were due to toxic substances from static blood within the isolated arterial segment, a protocol was performed in which blood was removed from the isolated segment. Again, neutrophil infiltration into the vessel was observed. Resting mean epicardial coronary artery blood flow before coronary occlusion was 19 +/- 3 ml/min; mean coronary blood flow 2.5 hours after reperfusion was identical at 19 +/- 3 ml/min. Response to both endothelial-dependent vasodilation (acetylcholine) and endothelial-independent vasodilation (nitroglycerin) challenges was normal early after reperfusion but was depressed late after reperfusion, suggesting progressive vascular dysfunction and hence a form of vascular reperfusion injury in this model. When large epicardial coronary arteries are deprived of blood flow, followed by reperfusion in this model, neutrophils migrate into the vessel wall as well as into the microvasculature. These abnormalities are associated with reduced endothelial-dependent and endothelial-independent coronary vasodilator reserve.