Venular Function Research Articles

Retinal endothelial function in cardiovascular risk patients: A randomized controlled exercise trial.

The aim of this study was to investigate, for the first time, the effects of high-intensity interval training (HIIT) on retinal microvascular endothelial function in cardiovascular (CV) risk patients. In the randomized controlled trial, middle-aged and previously sedentary patients with increased CV risk (aged 58±6years) with ≥ two CV risk factors were randomized into a 12-week HIIT (n=33) or control group (CG, n=36) with standard physical activity recommendations. A blinded examiner measured retinal endothelial function by flicker light-induced maximal arteriolar (ADmax) and venular (VDmax) dilatation as well as the area under the arteriolar (AFarea) and venular (VFarea) flicker curve using a retinal vessel analyzer. Standardized assessments of CV risk factors, cardiorespiratory fitness, and retinal endothelial function were performed before and after HIIT. HIIT reduced body mass index, fat mass, and low-density lipoprotein and increased muscle mass and peak oxygen uptake (VO2peak). Both ADmax (pre: 2.7±2.1%, post: 3.0±2.2%, P=.018) and AFarea (pre: 32.6±28.4%*s, post: 37.7±30.6%*s, P=.016) increased after HIIT compared with CG (ADmax, pre: 3.2±1.8%, post: 2.9±1.8%, P=.254; AFarea, pre: 41.6±28.5%*s, post: 37.8±27.0%*s, P=.186). Venular function remained unchanged after HIIT. There was a significant association between ∆-change VO2peak and ∆-changes ADmax and AFarea (P=.026, R2 =0.073; P=.019, R2 =0.081, respectively). 12-weeks of HIIT improved retinal endothelial function in middle-aged patients with increased CV risk independent of the reduction in classical CV risk factors. Exercise has the potential to reverse or at least postpone progression of small vessel disease in older adults with increased CV risk under standard medication. Dynamic retinal vessel analysis seems to be a sensitive tool to detect treatment effects of exercise interventions on retinal microvascular endothelial function in middle-aged individuals with increased CV risk.

Altered post-capillary and collecting venular reactivity in skeletal muscle with metabolic syndrome.

With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI2 bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A2 production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation. While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25μm (post-capillary) and ∼75μm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α1 - (and α2 -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to α1 -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3Hz were similar between strains. Venous production of TxA2 was higher in OZR than LZR and significantly higher than PGI2 production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome.

Treatment with Standard and Low Dose of Conjugated Equine Estrogen Differentially Modulates Estrogen Receptor Expression and Response to Angiotensin II in Mesenteric Venular Bed of Surgically Postmenopausal Hypertensive Rats.

Standard hormone therapy for menopausal women [conjugated equine estrogen (CEE) 0.625 mg] has been associated with increased risk of venous thrombosis. Regimens containing a lower CEE dose (0.30 mg) have been used clinically to decrease side effects of supraphysiologic doses of estrogen. In this study, we determined the effects of standard (SD) and low dose (LD) of CEE on venular function in ovariectomized (OVX) spontaneously hypertensive rats (SHR). Contractions by angiotensin-II (Ang-II 10 μM) in perfused mesenteric venular bed were markedly increased in OVX (21.5 ± 1.3 mmHg) compared with Sham (14.7 ± 1.1 mm Hg, P < 0.05). CEE-SD did not modify Ang-II responses in OVX, whereas CEE-LD restored Ang-II contraction to Sham levels. Endothelial nitric oxide synthase (eNOS) inhibition by L-NAME increased Ang-II contractions in Sham and CEE-LD and was without effect in venules of OVX SHR and CEE-SD. In OVX there was decreased NO generation in association with diminished eNOS phosphorylation and increased O2- generation in the venular wall. CEE-LD reverted the deleterious effects of ovariectomy. Although CEE-SD augmented eNOS phosphorylation in OVX, it was unable to increase NO levels, probably owing to its inability to reduce O2- Distinct effects by CEE-SD and CEE-LD parallel the differential modulation of Ang-II and estrogen receptors. Compared with Sham, CEE-LD increases Ang II receptor type 2, whereas CEE-SD modified ERβ expression in the venous bed. Interestingly, both CEE doses increased G protein-coupled estrogen receptor in OVX. Our data suggest that estrogen dose is an important factor for venous function. Although CEE-LD reversed deleterious effects of OVX, CEE-SD showed null effects despite its ability to increase eNOS activity.

Alterations to Venular Function in Skeletal Muscle with Metabolic Syndrome

While the overwhelming majority of research into vascular outcomes of the metabolic syndrome have focused on the arterial/arteriolar and capillary levels, investigation into venular function and how development of metabolic syndrome impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR) as compared to control leans (LZR), we determined indices of venular network structure as well as vessel structure and function. At ~17 weeks of age, skeletal muscle post‐capillary venular density was reduced by ~20% in LZR vs. OZR, although there was no evidence of remodeling of the wall of individual venules impacting passive diameter. Initial basal diameter and blood flow within individual venules of ~25 mm and ~ 60 mm diameter was similar between LZR and OZR, although an increased variability was evident. Dilator responses to acetylcholine were consistently blunted in venules of OZR vs. LZR, and this reflected multiple effects: including an oxidant stress‐based loss of venular nitric oxide bioavailability, an increased constrictor tone from TxA2 and an increased constrictor tone mediated via the α1 adrenergic receptor. Impaired dilator responses were also coupled to vessels where increased leukocyte adhesion/rolling was clearly present. Venular constrictor responses between LZR and OZR were comparable for angiotensin II, endothelin and α2 adrenoreceptor stimulation, although responses to α1 adrenoreceptor stimulation were mildly elevated, but with increased variability. In response to field stimulation of the cremaster muscle (0.5 or 1/s, 400 ms duration, 60 Hz within train, 7V), venular dilator and hyperemic responses to contraction were blunted in OZR vs. LZR, but responses at the higher frequency were similar in magnitude. These results suggest that alterations in venular function may contribute to dysregulation of flow distribution in skeletal muscle with metabolic syndrome and impair parameters of mass transport and exchange.Support or Funding InformationNational Institutes of Health; American Heart Association

Retinopathy in an obesity WHO III cohort: prevalence and risk factors

ObjectiveTo assess retinopathy and its risk factors in an obesity WHO III cohort.MethodsIn the Mannheim Obesity Study, 277 subjects with obesity WHO III aged 18–64 years were examined in a...

Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats.

Evolution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-α levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-α blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome.

Emerging Understanding of Roles for Arterioles in Inflammation

Arterioles, capillaries, and venules all actively change their cellular functions and phenotypes during inflammation in ways that are essential for maintenance of homeostasis and self-defense, and are also associated with many inflammatory disorders. ECs, together with pericytes and ECM proteins, can regulate blood flow, the coagulation cascade, fluid and solute exchange, and leukocyte trafficking. While capillary and venular functions in inflammation are well characterized, the arteriolar contribution to inflammation has only recently come into focus. Arterioles differ from venules in structure, EC morphology, shear environment, expression, and distribution of surface ligands; hence, regulation and function of arteriolar wall cells during inflammation may also be distinct from venules. Recent work indicates that in response to proinflammatory stimuli, arterioles alter barrier function, and support leukocyte and platelet interactions through upregulation of adhesion molecules. This suggests that in addition to their role in blood flow regulation, arterioles may also participate in inflammatory responses. In this review, we will discuss mechanisms that characterize arteriolar responses to proinflammatory stimuli. We will detail how distinct arteriolar features contribute to regulation of barrier function and leukocyte-EC interactions in inflammation, and further highlight the potential priming effects of arteriolar responses on venular function and progression of inflammatory responses.

Diagnostic Frequency Continuous Ultrasonography Directly Mitigates Venular Ischemia Reperfusion Damage

Our objective was to determine the effects of ischemia reperfusion (IR) treatment with continuous-mode diagnostic frequency ultrasonography exposure by assessing leukocyte-endothelial cell interactions, in terms of frequency and relative proportions of rolling and firmly attached leukocytes. Studies were carried out in the awake hamster chamber window preparation. Tourniquet ischemia was implemented by compressing a circular ring on the chamber window tissue for 4 hours, followed by reperfusion. Animals were randomly assigned into one of four groups as follows: IR; IR + ultrasonography; IR + N(omega)-nitro-L-arginine methyl ester (L-NAME); and IR + L-NAME + ultrasonography. Venules were exposed to epi-illumination, videorecorded, and leukocytes were categorized as "rolling"; flowing with endothelial contact; or "immobilized" cells, and counted during digital video-playback in 100-microm length segments. Leukocyte interaction with venular endothelium substantially decreased, during longterm reperfusion (p < 0.05) with ultrasonography exposure. Nitric oxide production inhibition, after L-NAME treatment, and ultrasonography exposure resulted in additional earlier substantially decreased leukocyte-endothelial cell interactions (p < 0.05). Venular function improvement, after IR damage, is a primary benefit derived from continuous-mode diagnostic frequency ultrasonography exposure. Although decreased interaction of adherent leukocytes can also be attributed to enhanced arteriolar flow, reduced interaction of rolling leukocytes is an immediate consequence of ultrasonography exposure.