Effectiveness of 1α-25-dihydroxyvitamin D3 active substance on anastomosis safety in the rat femoral artery end-to-end anastomosis experimental model: Macroscopic and histological analyses.

Under inflammatory conditions, macrophage dominance affects the degree of inflammation. We assessed the effects of the active vitamin D (calcitriol) administration on inflammatory processes and macrophage dominance and aimed to determine the potential positive macroscopic and histological effects in supermicrosurgical arterial anastomosis model of rats. Forty rats were divided into five groups: control surgery (Group 1), surgery with preoperative (Group 2), post-operative (Group 3), perioperative (Group 4) systemic calcitriol and surgery with local calcitriol (Group 5). Eighty femoral artery anastomoses were planned in both legs of rats. Systemic calcitriol was administered intraperitoneally daily to the animals in the relevant groups. Preoperative vessel diameter measurements were taken before anastomosis. Three weeks post-surgery, post-operative vessel diameter measurements were taken, anastomosis patency was assessed and vascular segments were collected for histological examination, which included assessment of M1 and M2 macrophage depolarisation, leucocyte infiltration, intima-media ratio and luminal gap scoring. Systemic calcitriol administration (pre-, post- or perioperative) significantly improved the vessel diameter (p < 0.001); there was no significant difference among Groups 2-4. Histological findings revealed that Groups 3 and 4 had lower intima-media ratios (p < 0.05 and p < 0.01), higher M2-M1 macrophage ratios (p < 0.01 and p < 0.001) and lower leucocyte infiltration (p < 0.05, p < 0.01 and p < 0.001). Local calcitriol administration had no vasodilatory effects or resulted in positive histological outcomes. Although the administration of calcitriol pre- and post-operatively increased the vessel diameter, the latter appeared to have a more favourable impact on the histological analyses.

Targeting endothelial KCa channels in vivo restores arterial and endothelial function in type 2 diabetic rats.

OBJECTIVE: This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats. BACKGROUND: Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo. METHODS: Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % â†’ 5 %). RESULTS: Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol. CONCLUSIONS: Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction.

Menstrual and oral contraceptive pill cycles minimally influence vascular function and associated cellular regulation in premenopausal females.

Historical exclusion of females in research has been, in part, due to the perceived influence of natural menstrual (NAT) and oral contraceptive pill (OCP) cycles on vascular outcomes. NAT and OCP cycle phases may influence brachial artery (BA) endothelial function, however, findings are mixed. Minimal research has examined arterial stiffness, smooth muscle, and lower limb endothelial function. The purpose of this study was to investigate the influence of NAT and OCP cycles on cardiovascular outcomes and cellular regulation. Forty-nine premenopausal females (n = 17 NAT, n = 17 second generation OCP, n = 15 third generation OCP) participated in two randomized order visits in the low (LH, early follicular/placebo) and high (HH, midluteal/active) hormone cycle phases. BA and superficial femoral artery (SFA) endothelial function [flow-mediated dilation (FMD) test], smooth muscle function (nitroglycerine-mediated dilation test), and carotid and peripheral (pulse wave velocity) arterial stiffness were assessed. Cultured female human endothelial cells were exposed to participant serum for 24 h to examine endothelial nitric oxide synthase (eNOS) and estrogen receptor-α (ERα) protein content. BA FMD was elevated in the HH vs. LH phase, regardless of group (HH, 7.7 ± 3.5%; LH, 7.0 ± 3.3%; P = 0.02); however, allometric scaling for baseline diameter resulted in no phase effect (HH, 7.6 ± 2.6%; LH, 7.1 ± 2.6%; P = 0.052, d = 0.35). SFA FMD, BA, and SFA smooth muscle function, arterial stiffness, and eNOS and ERα protein content were unaffected. NAT and OCP phases examined have minimal influence on vascular outcomes and ERα-eNOS pathway, apart from a small effect on BA endothelial function partially explained by differences in baseline artery diameter. NEW & NOTEWORTHY Comprehensive evaluation of the cardiovascular system in naturally cycling and second and third generation OCP users indicates no major influence of hormonal phases examined on endothelial function and smooth muscle function in the arteries of the upper and lower limbs, arterial stiffness, or underlying cellular mechanisms. Study findings challenge the historical exclusion of female participants due to potentially confounding hormonal cycles; researchers are encouraged to consider the hormonal environment in future study design.

Basal release and relaxation responses to 6-nitrodopamine in swine carotid, coronary, femoral, and renal arteries.

Mammalian and reptilian vascular tissues present basal release of 6-nitrodopamine, which is reduced when the tissues are pre-incubated with the NO synthase inhibitor L-NG-Nitro arginine methyl ester (L-NAME), or when the endothelium is mechanically removed. 6-Nitrodopamine induces vasorelaxation in pre-contracted vascular rings by antagonizing the dopaminergic D2-like receptor. Here it was investigated whether male swine vessels (including carotid, left descendent coronary, renal, and femoral arteries) release 6-nitrodopamine, dopamine, noradrenaline, and adrenaline, as measured by liquid chromatography coupled to tandem mass spectrometry. The in vitro vasorelaxant action of 6-nitrodopamine was evaluated in carotid, coronary, renal, and femoral arteries precontracted by U-46619 (3 nM), and compared to that induced by the dopamine D2-receptor antagonist L-741,626. Expression of tyrosine hydroxylase and the neuromaker calretinin was investigated by immunohistochemistry. All vascular tissues presented basal release of endothelium-derived catecholamines. The relaxation induced by 6-nitrodopamine was not affected by preincubation of the tissues with either L-NAME (100 µM, 30-min preincubation) or the heme-site inhibitor of soluble guanylyl cyclase ODQ (100 µM, 30-min preincubation). Electrical field stimulation (EFS)-induced contractions were significantly potentiated by previous incubation with L-NAME, but unaffected by ODQ preincubation. The contractions induced by EFS were reduced by preincubation with either 6-nitrodopamine or L-741,626. Immunohistochemistry in all arteries revealed the presence of tyrosine hydroxylase in the endothelium, whereas immunoreactivity for calretinin was negative. Swine vessels present basal release of endothelium-derived catecholamines and expression of tyrosine hydroxylase in the endothelium. The vasodilation induced by 6-nitrodopamine is due to blockade of dopaminergic D2-like receptors.

Dialdehyde starch cross-linked aminated gelatin sponges with excellent hemostatic performance and biocompatibility.

Developing a hemostatic material suitable for rapid hemostasis remains a challenge. This study presents a novel aminated gelatin sponge cross-linked with dialdehyde starch, exhibiting excellent biocompatibility and hemostatic ability. This aminated gelatin sponge features hydrophilic surface and rich porous structure with a porosity of up to 80 %. The results show that the aminated gelatin sponges exhibit superior liquid absorption capacity and can absorb up to 30-50 times their own mass of simulated body fluid within 5 min. Compared with the commercial gelatin hemostatic sponge and non-aminated gelatin hemostatic sponge, the aminated gelatin hemostatic sponge can accelerate the hemostatic process through electrostatic interactions, demonstrating superior hemostatic performance in both in vitro and in vivo hemostasis tests. The aminated gelatin sponge can effectively control the hemostatic time within 80 s in the in vivo rat femoral artery injury model, significantly outperforming both commercial and non-aminated gelatin sponges. In addition, the aminated gelatin sponge also exhibits good biocompatibility and certain antibacterial properties. The proposed aminated gelatin sponge has very good application prospects for the management of massive hemorrhage.

Biomimetic and Wound Microenvironment-Modulating PEGylated Glycopolypeptide Hydrogels for Arterial Massive Hemorrhage and Wound Prohealing.

Despite great progress in the hydrogel hemostats and dressings, they generally lack resistant vascular bursting pressure and intrinsic bioactivity to meet arterial massive hemorrhage and proheal wounds. To address the problems, we design a kind of biomimetic and wound microenvironment-modulating PEGylated glycopolypeptide hydrogels that can be easily injected and gelled in ∼10 s. Those glycopolypeptide hydrogels have suitable tissue adhesion of ∼20 kPa, high resistant bursting pressure of ∼150 mmHg, large microporosity of ∼15 µm, and excellent biocompatibility with ∼1% hemolysis ratio and negligible inflammation. They performed better hemostasis in rat liver and rat and rabbit femoral artery bleeding models than Fibrin glue, Gauze, and other hydrogels, achieving fast arterial hemostasis of <20 s and lower blood loss of 5-13%. As confirmed by in vivo wound healing, immunofluorescent imaging, and immunohistochemical and histological analyses, the mannose-modified hydrogels could highly boost the polarization of anti-inflammatory M2 phenotype and downregulate pro-inflammatory tumor necrosis factor-α to relieve inflammation, achieving complete full-thickness healing with thick dermis, dense hair follicles, and 90% collagen deposition. Importantly, this study provides a versatile strategy to construct biomimetic glycopolypeptide hydrogels that can not only resist vascular bursting pressure for arterial massive hemorrhage but also modulate inflammatory microenvironment for wound prohealing.

Integrated network pharmacology and metabolomics reveal vascular protective effects of Ilex pubescens on thromboangiitis obliterans.

BACKGROUND: Ilex pubescens Hook. et Arn (IP), traditionally known for its properties of promoting blood circulation, swelling and pain relief, heat clearing, and detoxification, has been used in the treatment of thromboangiitis obliterans (TAO). Despite its traditional applications, the specific mechanisms by which IP exerts its therapeutic effects on TAO remain unclear. AIM OF THE STUDY: This study aims to uncover the underlying mechanisms in the therapeutic effects of IP on TAO, employing network pharmacology and metabolomic approaches. METHODS: In this study, a rat TAO model was established by injecting sodium laurate through the femoral artery, followed by the oral administration of IP for 7 days. Plasma coagulation parameters were measured to assess the therapeutic effects of IP. The potential influence on the femoral artery and gastrocnemius muscle was histopathologically evaluated. Network pharmacology was employed to predict relevant targets and model pathways for TAO. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was used for the metabolic profile analysis of rat plasma. Immunohistochemistry (IHC) was used to verify the mechanisms by which IP promotes blood circulation in TAO. RESULTS: The study revealed that IP improved blood biochemical function in TAO and played a significant role in vascular protection and maintaining normal blood vessels and gastrocnemius morphologies. Network pharmacology showed that IP compounds play a therapeutic role in modulating lipids and atherosclerosis. Metabolomic analysis revealed that the pathways involved in sphingolipid metabolism and steroid biosynthesis were significantly disrupted. The joint analysis showed a strong correlation between lysophosphatidylcholine and IP components, including triterpenoid and iridoid components, which support the curative action of IP through the modulation of sphingolipid metabolism. Furthermore, decreased expression levels of SPHK1/S1PR1, TNF-α, IL-1ß, and IL-6 were observed in the IP-treated group, suggesting that IP exerts a protective effect on the vasculature primarily by regulating of the SPHK1/S1PR1 signaling pathway. CONCLUSION: In this study, we found that IP protects the vasculature against injury and treats TAO by regulating the steady-state disturbance of the sphingolipid pathway. These findings suggest that IP promotes vasculature by modulating sphingolipid metabolism and SPHK1/S1PR1 signaling pathway and reduce levels of inflammatory factors, offering new insights into its therapeutic potential.

The antidiabetic drug ipragliflozin induces vasorelaxation of rabbit femoral artery by activating a Kv channel, the SERCA pump, and the PKA signaling pathway.

We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 µM), the inwardly rectifying K+ channel inhibitor Ba2+ (50 µM), or the Ca2+-sensitive K+ channel inhibitor paxilline (10 µM) did not influence the vasorelaxant effect. However, the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect. Specifically, the vasorelaxant response to ipragliflozin was significantly attenuated by pretreatment with the Kv7.X channel inhibitors linopirdine (10 µM) and XE991 (10 µM), the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 µM) and cyclopiazonic acid (10 µM), and the cAMP/protein kinase A (PKA)-associated signaling pathway inhibitors SQ22536 (50 µM) and KT5720 (1 µM). Neither the cGMP/protein kinase G (PKG)-associated signaling pathway nor the endothelium was involved in ipragliflozin-induced vasorelaxation. We conclude that ipragliflozin induced vasorelaxation of rabbit femoral arteries by activating Kv channels (principally the Kv7.X channel), the SERCA pump, and the cAMP/PKA-associated signaling pathway independent of other K+ (ATP-sensitive K+, inwardly rectifying K+, and Ca2+-sensitive K+) channels, cGMP/PKG-associated signaling, and the endothelium.

Local, Downstream, and Systemic Evaluation after Femoral Artery Angioplasty with Kanshas Drug-Coated Balloons In Vitro and in a Healthy Swine Model.

PURPOSE: To evaluate the incidence of distal embolism and local vascular responses after treatment with the Kanshas drug-coated balloon (DCB) in a preclinical model. MATERIALS AND METHODS: A total of 90 femoral arteries from 35 healthy swine were treated with a single-dose (×1) or triple-dose (×3) Kanshas DCB that applies the Unicoat technology with 3.2 µg/mm2 of paclitaxel. An uncoated Kanshas balloon was used as a control. The arterial wall, downstream skeletal muscle, and nontarget organs (kidneys, lungs, lymph nodes, liver, spleen, and heart) were histologically evaluated. For pharmacokinetic evaluation, a total of 40 healthy swine were treated with ×1 Kanshas DCB, and treated vessels were evaluated ex vivo with high-performance liquid chromatography-mass spectrometry. RESULTS: Arteries treated with the Kanshas DCB showed mild proteoglycan deposition accompanied by the loss of smooth muscle cells (SMCs). These changes increased in a dose-dependent manner (medial SMC loss at 28 days in the ×1 vs ×3 groups, in depth, 1 (0.75-1.38) vs 2 (1.63-2.44); P = .0008; in circumference, 0.83 (0.67-1) vs 1.5 (1.19-1.81); P = .0071). No evidence of distal embolization in skeletal muscles (0 of 210 histological sections) and nontarget organs (0 of 345 sections) was observed. The pharmacokinetic evaluation showed high paclitaxel concentration in the treated artery (912 ng/mg, peaking at 3 minutes), which remained detectable at up to 180 days (0.04 ng/mg). CONCLUSIONS: The Kanshas DCB showed a local drug effect in treated arteries up to 180 days with a high concentration of paclitaxel and no histological evidence of distal embolization.

Toxic Metals and Subclinical Atherosclerosis in Carotid, Femoral, and Coronary Vascular Territories: The Aragon Workers Health Study.

OBJECTIVE: Studies evaluating the association of metals with subclinical atherosclerosis are mostly limited to carotid arteries. We assessed individual and joint associations of nonessential metals exposure with subclinical atherosclerosis in 3 vascular territories. Approach and Results: One thousand eight hundred seventy-three Aragon Workers Health Study participants had urinary determinations of inorganic arsenic species, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten. Plaque presence in carotid and femoral arteries was determined by ultrasound. Coronary Agatston calcium score ≥1 was determined by computed tomography scan. Median arsenic, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten levels were 1.83, 1.98, 0.27, 1.18, 0.05, 9.8, 0.03, 0.66, and 0.23 µg/g creatinine, respectively. The adjusted odds ratio (95% CI) for subclinical atherosclerosis presence in at least one territory was 1.25 (1.03-1.51) for arsenic, 1.67 (1.22-2.29) for cadmium, and 1.26 (1.04-1.52) for titanium. These associations were driven by arsenic and cadmium in carotid, cadmium and titanium in femoral, and titanium in coronary territories and mostly remained after additional adjustment for the other relevant metals. Titanium, cadmium, and antimony also showed positive associations with alternative definitions of increased coronary calcium. Bayesian Kernel Machine Regression analysis simultaneously evaluating metal associations suggested an interaction between arsenic and the joint cadmium-titanium exposure. CONCLUSIONS: Our results support arsenic and cadmium and identify titanium and potentially antimony as atherosclerosis risk factors. Exposure reduction and mitigation interventions of these metals may decrease cardiovascular risk in individuals without clinical disease.

3D modelling of drug-coated balloons for the treatment of calcified superficial femoral arteries.

BACKGROUND/OBJECTIVES: Drug-coated balloon therapy for diseased superficial femoral arteries remains controversial. Despite its clinical relevance, only a few computational studies based on simplistic two-dimensional models have been proposed to investigate this endovascular therapy to date. This work addresses the aforementioned limitation by analyzing the drug transport and kinetics occurring during drug-coated balloon deployment in a three-dimensional geometry. METHODS: An idealized three-dimensional model of a superficial femoral artery presenting with a calcific plaque and treated with a drug-coated balloon was created to perform transient mass transport simulations. To account for the transport of drug (i.e. paclitaxel) released by the device, a diffusion-reaction equation was implemented by describing the drug bound to specific intracellular receptors through a non-linear, reversible reaction. The following features concerning procedural aspects, pathologies and modelling assumptions were investigated: (i) balloon application time (60-180 seconds); (ii) vessel wall composition (healthy vs. calcified wall); (iii) sequential balloon application; and (iv) drug wash-out by the blood stream vs. coating retention, modeled as exponential decay. RESULTS: The balloon inflation time impacted both the free and specifically-bound drug concentrations in the vessel wall. The vessel wall composition highly affected the drug concentrations. In particular, the specifically-bound drug concentration was four orders of magnitude lower in the calcific compared with healthy vessel wall portions, primarily as a result of reduced drug diffusion. The sequential application of two drug-coated balloons led to modest differences (~15%) in drug concentration immediately after inflation, which became negligible within 10 minutes. The retention of the balloon coating increased the drug concentration in the vessel wall fourfold. CONCLUSIONS: The overall findings suggest that paclitaxel kinetics may be affected not only by the geometrical and compositional features of the vessel treated with the drug-coated balloon, but also by balloon design characteristics and procedural aspects that should be carefully considered.

Vascular region-specific changes in arterial tone in rats with type 2 diabetes mellitus: Opposite responses of mesenteric and femoral arteries to acetylcholine and 5-hydroxytryptamine.

AIMS: Type 2 diabetes mellitus (T2DM) ranks in the top 10 causes of mortality worldwide. The key factor of T2DM vascular complications is endothelial dysfunction. It is characterized by the vessels motor activity disruption and endothelium-derived factors imbalance. The blood vessels morphological and molecular heterogeneity greatly affects the changes occurring in T2DM. Therefore, we conducted a comparative study of vascular bed changes occurring in T2DM. MAIN METHODS: Male Wistar rats were fed a high-fat diet for 20 weeks, followed by a single streptozotocin injection (20 mg/kg). T2DM was confirmed with an oral glucose tolerance test. KEY FINDINGS: A dose-dependent contraction study showed an increase in third-order mesenteric arterioles response to serotonin but not to phenylephrine. These vessels also exhibited a decrease in acetylcholine-dependent relaxation and an increase in guanylate cyclase function. At the same time, the femoral arteries showed a tendency for increased acetylcholine-dependent relaxation. The blood plasma analysis revealed low bioavailable nitric oxide and high levels of endothelin-1 and ROS. SIGNIFICANCE: This knowledge, in conjunction with the features of the T2DM course, can allow further targeted approaches development for the prevention and treatment of vascular complications occurring in the disease.

Roles of vascular endothelial and smooth muscle cells in the vasculoprotective effect of insulin in a mouse model of restenosis.

BACKGROUND: Insulin exerts vasculoprotective effects on endothelial cells (ECs) and growth-promoting effects on vascular smooth muscle cells (SMCs) in vitro, and suppresses neointimal growth in vivo. Here we determined the role of ECs and SMCs in the effect of insulin on neointimal growth. METHODS: Mice with transgene CreERT2 under the control of EC-specific Tie2 (Tie2-Cre) or SMC-specific smooth muscle myosin heavy chain promoter/enhancer (SMMHC-Cre) or littermate controls were crossbred with mice carrying a loxP-flanked insulin receptor (IR) gene. After CreERT2-loxP-mediated recombination was induced by tamoxifen injection, mice received insulin pellet or sham (control) implantation, and underwent femoral artery wire injury. Femoral arteries were collected for morphological analysis 28 days after wire injury. RESULTS: Tamoxifen-treated Tie2-Cre+ mice showed lower IR expression in ECs, but not in SMCs, than Tie2-Cre- mice. Insulin treatment reduced neointimal area after arterial injury in Tie2-Cre- mice, but had no effect in Tie2-Cre+ mice. Tamoxifen-treated SMMHC-Cre+ mice showed lower IR expression in SMCs, but not in ECs, than SMMHC-Cre- mice. Insulin treatment reduced neointimal area in SMMHC-Cre- mice, whereas unexpectedly, it failed to inhibit neointima formation in SMMHC-Cre+ mice. CONCLUSION: Insulin action in both ECs and SMCs is required for the "anti-restenotic" effect of insulin in vivo.

Albumin covering maintains endothelial function upon magnetic iron oxide nanoparticles intravenous injection in rats.

Magnetic iron oxide nanoparticles (IONP) present the promising instrument for broad-spectrum of clinical applications, for example, targeted drug delivery. Reactivity of nanoparticles depends on their surface area and material. In the blood plasma IONP are getting covered with an albumin crown, so it was decided to test this shell for biocompatibility. Male Wistar rats were anesthetized and underwent laparotomy. Abdominal aorta was connected to external hemodynamic loop with regulated blood flow. Hind body quarter got step-like blood flow changing from 30 to 150 mmHg and back. This was followed with i.v. injection of IONP, albumin solution or albumin-covered IONP and consequent similar flow changes. Central hemodynamics-heart rate and mean arterial pressure were registered throughout the experiment and no significant changes in these parameters were observed. Hind paw microcirculation level had the same dynamic in all groups under changing blood flow conditions. At the end, venous blood was collected for endothelin-1 and NO evaluation that showed similar changes and no endothelial damage. Mesenteric arteries and femoral artery reactivity were evaluated with wire myography. Mesenteric arteries had the most relaxing function preservation after albumin-covered IONP injection. Given data reveal advantage of albumin-coated IONP so this can be used for further investigations as a vascular-safe vehicle.

Vascular Response of a Polymer-Free Paclitaxel-Coated Stent (Zilver PTX) versus a Polymer-Coated Paclitaxel-Eluting Stent (Eluvia) in Healthy Swine Femoropopliteal Arteries.

PURPOSE: To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia). MATERIALS AND METHODS: Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months. RESULTS: Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs. CONCLUSIONS: Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.

Imatinib improves insulin resistance and inhibits injury-induced neointimal hyperplasia in high fat diet-fed mice.

Imatinib, a PDGF receptor tyrosine kinase inhibitor, has been shown to suppress intimal hyperplasia in different animal models under normal metabolic milieu, diabetic, and/or hypercholesterolemic conditions. However, the impact of imatinib treatment on injury-induced neointimal hyperplasia has not yet been investigated in the setting of insulin resistance without frank diabetes. Using a mouse model of high fat diet (HFD)-induced insulin resistance and guidewire-induced arterial injury, the present study demonstrates that intraperitoneal administration of imatinib (25 mg/kg/day) for ~3 weeks resulted in a marked attenuation of neointimal hyperplasia (intima/media ratio) by ~78% (n = 6-9 per group; P < 0.05). Imatinib treatment also led to significant improvements in key metabolic parameters. In particular, imatinib improved insulin resistance and glucose tolerance, as revealed by complete inhibition of HFD-induced increase in HOMA-IR index and AUCIPGTT, respectively. In addition, imatinib treatment led to diminutions in HFD-induced increases in plasma total cholesterol and triglycerides by ~73% and ~59%, respectively. Furthermore, imatinib decreased HFD-induced increase in visceral fat accumulation by ~51% (as determined by epididymal white adipose tissue weight). Importantly, imatinib treatment in HFD-fed mice enhanced plasma levels of high-molecular-weight adiponectin by ~2-fold without affecting total adiponectin. However, there were no significant changes in mean arterial pressure in insulin-resistant state or after imatinib exposure, as measured by tail-cuff method. Together, the present findings suggest that targeting PDGF receptor tyrosine kinase using imatinib may provide a realistic treatment option to prevent injury-induced neointimal hyperplasia and diet-induced insulin resistance in obesity.

Different Responses of Arterial Stiffness between the Aorta and the Iliofemoral Artery during the Administration of Phentolamine and Atenolol in Rabbits.

AIM: The mechanism underlying the stiffness of the aorta and iliofemoral artery that is required to maintain blood pressure (BP) is unclear. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was defined by applying the cardio-ankle vascular index (CAVI). We compared changes in stiffness of the two arteries in response to reduced BP, due to the non-selective α adrenergic blocker phentolamine and the ß1 adrenergic blocker atenolol, in rabbits. METHODS: Pressure waves at the origin (oA) and distal ends of the aorta (dA) and the distal end of the left femoral artery (fA) were recorded simultaneously using three pressure sensors in 25 anesthetized rabbits. Phentolamine (50 µg/kg/min) and atenolol (10 mg/kg/min) were infused for 2 min. The pulse wave velocity (PWV) in each artery was determined; aBeta, ifBeta, and whole Beta (aifBeta) were calculated by the following formula; Beta=2ρ/PP×ln(SBP/DBP)×PWV2 (ρ: blood density; SBP, SBP, and PP: systolic, diastolic, and pulse pressures, respectively). RESULTS: SBP and DBP at oA, dA, and fA decreased by the administration of phentolamine and atenolol, with and without decreased total peripheral vascular resistance. After phentramine infusion, cardiac output (CO), aBeta, and aifBeta increased, while ifBeta decreased. After infusion of atenolol, CO decreased, while aBeta, ifBeta, and aifBeta remained unchanged. CONCLUSION: The contradictory reactions of aBeta and ifBeta to phentolamine suggest that the stiffness of the aorta and ilio-femoral artery is regulated separately during decreased BP induced by phentolamine, but not by atenolol.

Aldosterone Induces Vasoconstriction in Individuals with Type 2 Diabetes: Effect of Acute Antioxidant Administration.

CONTEXT: Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species-dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone. OBJECTIVE: We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared with healthy controls and if infusion of an antioxidant (n-acetylcysteine [NAC]) would alter the vascular response. METHODS: In a case-control design, 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min-1 [L leg volume]-1) for 10 minutes into the femoral artery with and without coinfusion of NAC (125 mg kg-1 hour-1 followed by 25 mg kg-1 hour-1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected. RESULTS: Compared with the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in individuals with type 2 diabetes, whereas coinfusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions. CONCLUSION: These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response.

Differential Contractile Reactivity to Nucleotides in Femoral Arteries of OLETF and LETO Rats.

Extracellular nucleotides play an important role in the regulation of vascular function, and an abnormal vascular function is an important participant in the development and progression of diabetic vascular complications. The purpose of this study was to determine whether contractile responses induced by extracellular nucleotides and a dinucleotide, uridine adenosine tetraphosphate (Up4A), in femoral arteries would be altered at the chronic stage of type 2 diabetes. We determined the changes in contractile reactivity induced by ATP, uridine triphosphate (UTP), uridine diphosphate (UDP), and Up4A in the femoral arteries of Otsuka Long-Evans Tokushima Fatty (OLETF) rats (aged male type 2 diabetic rats) and, Long-Evans Tokushima Otsuka (LETO) rats (controls for OLETF rats). ATP-induced contractions were greater in OLETF rats than in LETO rats. UTP-induced contractions were lower in OLETF rats than in LETO rats. UDP- and Up4A-induced contractions were similar between OLETF and LETO rats. The femoral artery contractile changes induced by the extracellular nucleotides and dinucleotide were similar when nitric oxide synthase was inhibited. These results suggest that the extent of femoral artery contractile reactivity to nucleotides/dinucleotides differs during long-term duration of type 2 diabetes.

Vascular dysfunction and oxidative stress caused by acute formaldehyde exposure in female adults.

Formaldehyde (FA) is a common, volatile organic compound used in organic preservation with known health effects of eye, nose, and throat irritation linked to oxidative stress and inflammation. Indeed, long-term FA exposure may provoke skin disorders, cancer, and cardiovascular disease. However, the effects of short-term FA exposure on the vasculature have yet to be investigated. We sought to investigate the impact of an acute FA exposure on 1) macrovascular function in the arm (brachial artery flow-mediated dilation, FMD), 2) microvascular function in the arm (brachial artery reactive hyperemia, RH) and leg (common femoral artery, supine passive limb movement, PLM), and 3) circulating markers of oxidative stress (xanthine oxidase, XO; protein carbonyl, PC; and malondialdehyde, MDA) and inflammation (C-reactive protein, CRP). Ten (n = 10) healthy females (23 ± 1 yr) were studied before and immediately after a 90-min FA exposure [(FA): 197 ± 79 ppb] in cadaver dissection laboratories. Brachial artery FMD% decreased following FA exposure (Pre-FA Exp: 9.41 ± 4.21%, Post-FA Exp: 6.74 ± 2.57%; P = 0.043), and FMD/shear decreased following FA exposure (Pre-FA Exp: 0.13 ± 0.07 AU, Post-FA Exp: 0.07 ± 0.03 AU; P = 0.016). The area under the curve for brachial artery RH (Pre-FA Exp: 481 ± 191 ml, Post-FA Exp: 499 ± 165 ml) and common femoral artery PLM (Pre-FA Exp: 139 ± 95 ml, Post-FA Exp: 129 ± 64 ml) were unchanged by FA exposure (P > 0.05). Circulating MDA increased (Pre-FA Exp: 4.8 ± 1.3 µM, Post-FA Exp: 6.3 ± 2.2 µM; P = 0.047) while XO, PC, and CRP were unchanged by FA exposure (P > 0.05). These initial data suggest a short FA exposure can adversely alter vascular function and oxidative stress, influencing cardiovascular health.NEW & NOTEWORTHY This study was the first to investigate the implications of acute formaldehyde (FA) exposure on adult female vascular function in the arms and legs. The main findings of this study were a decrease in conduit vessel function without any alteration to microvascular function following a 90-min FA exposure. Additionally, the oxidative stress marker malondialdehyde increased after FA exposure. Taken together, these results suggest acute FA exposure have deleterious implications for the vasculature and redox balance.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/formaldehyde-exposure-decreases-vascular-function/.