Constriction Of Vessels Research Articles

Experimental and numerical investigation on the transient vascular thermal response to multi-pulse Nd:YAG laser.

Port wine stains (PWS) are congenital vascular malformations that progressively darken and thicken with age. Laser therapy is currently the most effective way in clinical practice for PWS. A 1,064 nm Nd:YAG laser in the near-infrared band can achieve a deeper treatment depth compared to the current widely adopted pulsed dye laser. However, because of its relatively weak absorption by blood, single-pulse Nd:YAG laser requires high energy density to cause effective vessel damage, but may inflict undesirable burning to surrounding collagen. Multi-pulse laser has great potential in clinical treatment because it needs less energy density for each pulse. This paper presented an experimental and theoretical study of the transient thermal effects of low-energy multi-pulse Nd:YAG laser on blood vessels. In vivo experiments were performed on dorsal skin chamber. By using a high speed camera (up to 2,000 fps), the complete and dynamic thermal response of blood vessels during laser irradiation and between pulse intervals was obtained. In vitro experiment in capillary tubes and Numerical simulations by two-scale heat transfer model were also conducted to further explore the in vivo experimental findings. The complete and dynamic response of blood vessels were obtained, including vessel dilation, thrombus formation, partial vessel constriction, thread-like constriction, cavitation and bubbles, and hemorrhage. Thread-like constriction is the desirable treatment end point, which will only occur after thrombus completely occludes the vessel lumen. Cavitation can cause hemorrhage when thrombus fails to occlude the vessel lumen. In vitro experiment found that vessel constriction was due to the constriction of thrombus induced by laser irradiation. Theoretical investigation revealed that the mechanism for the effective reduction of energy density by multi-pulse Nd:YAG laser was due to enhanced light absorption of the blood with thrombus formation. For multi-pulse treatment, laser parameters are recommended as repetition rate of 10 Hz and pulse number of 10. The incident energy in each pulse should be strong enough to induce blood coagulation through seven or eight pulses and should be lower than the threshold of blood cavitation. Lasers Surg. Med. 49:852-865, 2017. © 2017 Wiley Periodicals, Inc.

Pericytes impair capillary blood flow and motor function after chronic spinal cord injury.

Blood vessels in the central nervous system (CNS) are controlled by neuronal activity; for example, widespread vessel constriction (vessel tone) is induced by brainstem neurons that release the monoamines serotonin and noradrenaline, and local vessel dilation is induced by glutamatergic neuron activity. Here, we examined how vessel tone adapts to the loss of neuron-derived monoamines after spinal cord injury (SCI) in rats. We find that, months after the imposition of SCI, the spinal cord below the site of injury is in a chronic state of hypoxia, due to paradoxical excess activity of monoamine receptors (5-HT1) on pericytes, despite the absence of monoamines. This monoamine receptor activity causes pericytes to locally constrict capillaries, reducing blood flow to ischemic levels. Receptor activation in the absence of monoamines results from the production of trace amines (such as tryptamine) by pericytes that ectopically express the enzyme aromatic-l-amino-acid-decarboxylase (AADC), which synthesizes trace amines directly from dietary amino acids (such as tryptophan). Inhibition of monoamine receptors or of AADC, or even increased inhaled oxygen, produces substantial relief from hypoxia and improves motoneuron and locomotor function after SCI.

Chronic cocaine induces HIF-VEGF pathway activation along with angiogenesis in the brain.

Cocaine induces vasoconstriction in cerebral vessels, which with repeated use can result in transient ischemic attacks and cerebral strokes. However, the neuroadaptations that follow cocaine’s vasoconstricting effects are not well understood. Here, we investigated the effects of chronic cocaine exposure (2 and 4 weeks) on markers of vascular function and morphology in the rat brain. For this purpose we measured nitric oxide (NO) concentration in plasma, brain neuronal nitric oxide synthase (nNOS or NOS1), HIF-1α, and VEGF expression in different brain regions, i.e., middle prefrontal cortex, somatosensory cortex, nucleus accumbens, and dorsal striatum, using ELISA or Western blot. Additionally, microvascular density in these brain regions was measured using immunofluorescence microscopy. We showed that chronic cocaine significantly affected NOS1, HIF-1α and VEGF expression, in a region- and cocaine treatment-time- dependent manner. Cerebral microvascular density increased significantly in parallel to these neurochemical changes. Furthermore, significant correlations were detected between VEGF expression and microvascular density in cortical regions (middle prefrontal cortex and somatosensory cortex), but not in striatal regions (nucleus accumbens and dorsal striatum). These results suggest that following chronic cocaine use, as cerebral ischemia developed, NOS1, the regulatory protein to counteract blood vessel constriction, was upregulated; meanwhile, the HIF-VEGF pathway was activated to increase microvascular density (i.e., angiogenesis) and thus restore local blood flow and oxygen supply. These physiological responses were triggered presumably as an adaptation to minimize ischemic injury caused by cocaine. Therefore, effectively promoting such physiological responses may provide novel and effective therapeutic solutions to treat cocaine-induced cerebral ischemia and stroke.

Retinal vessel diameters and reactivity in diabetes mellitus and/or cardiovascular disease

BackgroundRetinal vessel calibre and vascular dilation/constriction in response to flicker light provocation may provide a measure distinguishing patients suffering from diabetes mellitus and/or cardiovascular disease.MethodsOne hundred and sixteen age and sex matched patients with diabetes mellitus (DM), cardiovascular disease (CVD) and both DM and CVD (DM + CVD) underwent systemic and intraocular pressure measurements. Retinal vessel calibres were assessed using a validated computer-based program to compute central retinal artery and vein equivalents (CRVE) from monochromatic retinal images. Vessel dilation and constriction responses to flicker light provocation were assessed by continuous retinal vessel diameter recordings. Plasma endothelial markers von Willebrand factor (vWf) and soluble E selectin (sEsel) were measured by ELISA.ResultsRetinal vessel calibres were comparable across groups but CRVE correlated significantly with disease duration in DM patients (r = 0.57, p < 0.001). Patients suffering DM only exhibited reduced arterial vasomotion at rest and reduced arterial constriction following flicker light induced vessel dilation compared to patients with CVD and those suffering both CVD + DM (p = 0.030). Patients suffering from CVD + DM exhibited significant differences between each flicker cycle in regards to arterial maximum constriction (p = 0.006) and time needed to reach arterial maximum dilation (p = 0.004), whereas the other two groups did not show such inconsistencies between individual flicker cycles. vWf was raised in CVD + DM compared to the other two groups (p ≤ 0.02), whilst sEsel was raised in CVD + DM compared to DM alone (p = 0.044).ConclusionsDynamic retinal vascular calibres as obtained by continuous diameter measurements using flicker light provocation can reveal subtle differences between groups suffering from CVD with and without DM. This difference in reaction pattern and lack of arterial constriction in DM may provide a suitable marker to monitor progression.

Traumatic brain injury impairs myogenic constriction of cerebral arteries: role of mitochondria‐derived H2O2, TRPV4 and calcium‐activated potassium channels

Traumatic brain injury (TBI) impairs pressure‐induced myogenic constriction of cerebral arteries, which contributes to TBI‐related autoregulatory dysfunction and the development of secondary brain injury. TBI has been shown to lead to mitochondrial oxidative stress in cerebral vessels, which likely contributes to secondary brain injury, as well. We tested the hypothesis that TBI‐induced mitochondrial oxidative stress contributes to the impaired myogenic response of cerebral arteries after TBI and aimed to establish the underlying mechanisms. We induced traumatic brain injury in WKY rats using the weight‐drop technique, and 24 hours after severe TBI we found that myogenic responses of isolated middle cerebral arteries (MCAs) of TBI rats were blunted compared to control. The impaired myogenic responses of MCAs were restored after inhibiting mitochondrial oxidative stress (mitoTEMPO), eliminating H2O2 (PEG catalase) and blocking large‐conductance calcium‐activated potassium (BKCa) channels and transient receptor activated vanilloid channel 4 (TRPV4). We also found that H2O2‐induced dilation of MCAs involves the activation of BKCa and TRPV4 channels, and that H2O2‐induced BK currents on vascular smooth muscle cells depend on the activation of TRPV4 channels. Our results suggest that after TBI excessive mitochondria‐derived H2O2 activates BKCa channels via TRPV4 channel activation in the cerebrovascular wall, which diminishes pressure‐induced constriction of cerebral vessels. Future studies should elucidate the potential of inhibiting these vascular pathways to restore autoregulatory function after TBI in order to prevent TBI‐related secondary brain damage in patients suffered traumatic brain injury.Support or Funding InformationThis work was supported by grants from the Marie Curie Actions SMARTER 7th Framework Program of the European Union 606998 (to NSz and AK), the Hungarian Academy of Sciences (the Bolyai Research Scholarship BO/00634/15 to PT), the Hungarian Brain Research Program (Grant No. KTIA_13_NAP‐A‐II/8 to PT, ECz and AB), National Center for Complementary and Alternative Medicine (R01‐AT006526 to ZU) and the Hungarian Scientific Research Fund (K108444 to AK).

Diving Mice vs. Torpid Mice: A Comparison of Cardiovascular Regulation

The diving response is a coordinated physiological response to submersion into water, and is used widely amongst mammals. The physiological response is composed of three primary effects: an immediate drop in heart rate, a reduced drive to breathe, and constriction of peripheral blood vessels. The diving response is important, not only because of its dramatic influence of the autonomic nervous system, but also because it inhibits or alters normal homeostatic reflexes such as the drive to breathe. We hypothesized that the cardiovascular effects and neural circuitry involved in the murine dive response are similar to those used in daily torpor. In this study, telemeters that measure arterial pressure and body temperature were implanted into female C57Bl/6J mice. These mice were trained to swim then voluntarily dive underwater for a distance of 60 cm over a 5 second period. After a recovery period, the same mice were calorically restricted to induce a bout of torpor. Just before the dive, the interbeat interval (IBI) was 87±3 msec and diastolic pressure was 100±8 mmHg. Diving caused a dramatic bradycardia immediately at the onset of each dive (IBI increased to 464±60 msec) and diastolic pressure dropped to 56±9 mmHg, that coincided with elevated peripheral resistance. Mice experienced a short bout (~5 sec) hypertension (diastolic pressure rose to 133±9 mmHg) upon emergence. The bradycardia and hypotension were dependent on vagal influence, as pre‐treatment with atropine blocked these responses. The same absolute changes to heart rate, blood pressure, and total peripheral resistance were observed in the torpid mouse, albeit at a different time scale. These data suggest that the drivers of the cardiovascular changes during a bout of torpor and during the diving response are likely shared.Support or Funding InformationSupported by 1R15HL120072‐01A1 to SJS

Effects of neuropeptide Y on coronary artery vasomotion in patients with microvascular angina

BackgroundPatients with microvascular angina (exertional angina, positive exercise tests and normal coronary arteriograms) usually have a reduced coronary blood flow reserve. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor involved in modulation of coronary vasomotor tone and may play a role in microvascular angina. MethodsWe compared the effects of NPY (0.2–1.0pmol/kg, intracoronary) on the vasomotor response of proximal and distal segments of the coronary arteries in 7 patients with microvascular angina, 9 with chronic stable angina, and 9 control individuals. The coronary response to the administration of ergonovine was also assessed in 9 other patients with microvascular angina. Computerized coronary artery diameter measurements were carried out before (baseline) and after the administration of the vasoactive agents. ResultsMean baseline coronary lumen diameters were similar in control, microvascular angina, and coronary artery disease patients. NPY constricted proximal coronary segments by 8±2%, 5±2% and 6±3% and distal segments by 14±2%, 11±2% and 10±2% in control, microvascular angina, and coronary artery disease patients, respectively (p=NS between groups). In patients with microvascular angina, ergonovine constricted proximal coronary segments by 7±1.5% and distal segments by 12.5±3% (p=NS vs. NPY). During NPY administration four microvascular angina patients developed chest pain, ST segment depression, and a marked lengthening of the contrast medium run off, in the absence of epicardial coronary artery spasm. Control individuals and coronary artery disease patients did not experience chest pain, ST segment shifts, or lengthening of the run off during NPY administration. Ergonovine administration caused chest pain and lengthening of the contrast run-off, in the absence of epicardial coronary artery spasm, in one microvascular angina patient. ConclusionsExogenous NPY causes mild epicardial coronary artery constriction which is similar in patients with non-cardiac chest pain, microvascular angina and coronary artery disease. Myocardial ischemia and marked lengthening of the contrast run off in response to NPY occurred in microvascular angina patients but not in control or coronary artery disease patients. An abnormal constrictor response to NPY at the microcirculation level could be the mechanism underlying the ischemic manifestations observed in patients with microvascular angina. Condensed abstract (table of contents)The vasomotor response of proximal and distal coronary artery segments was studied in twenty five patients: 7 microvascular angina, 9 chronic stable angina, and 9 control subjects. Computerized measurements of coronary diameters were carried out before and after the intracoronary administration of neuropeptide Y (NPY) and ergonovine. Constriction of epicardial arteries in response to NPY was mild and not significantly different in control, microvascular angina and coronary artery disease patients. Ergonovine-induced epicardial coronary artery constriction was similar to that of NPY. However, NPY caused transient myocardial ischemia in patients with microvascular angina (probably through constriction of the small intramyocardial vessels), but not in control subjects or coronary artery disease patients.

Hypertension management: Old drug revisited - Cilnidipine

Cilnidipine is a promising fourth-generation calcium channel blocker which along with inhibition of the L-type Ca 2+ channels in vascular smooth muscle cells, also inhibits the N-type Ca 2+ channels in sympathetic neurons. As a result, in addition to hypotensive action secondary to vascular relaxation, it also demonstrates significant sympatholytic action, whereby it attenuates platelet activation (and consequent arterial thrombosis), tachycardia, oxidative stress, and also inhibits activation of renin-angiotensin system in blood vessels. By virtue of the latter effect, they relieve constriction of postglomerular vessels and thereby ameliorate glomerular hypertension and render renoprotective effect. Besides these, cilnidipine also improves insulin resistance, nitric oxide production, and protects against retinal neuronal injury. Thus, it is expected to be a very useful addition in the current armamentarium for the treatment of hypertension.

Purtscher-like Retinopathy Associated with High Altitude Travel

Purpose To report a case of Purtscher-like retinopathy associated with travel at high altitude. Methods Case report. Results A 67-year-old man presented 2 weeks after acute vision loss in his left eye that occurred while he was hiking in the mountains of South America. Funduscopic examination revealed multiple cotton-wool spots and discrete areas of retinal whitening. Fluorescein angiography demonstrated areas of choroidal fluorescence blocked by retinal whitening, delayed arteriovenous transit time, and late capillary leakage. Spectral-domain optical coherence tomography showed hyperreflectivity in the inner plexiform, inner nuclear, and outer plexiform layers localized to the areas of retinal whitening. These findings were believed to be most consistent with Purtscher flecken, and the patient was diagnosed with Purtscher-like retinopathy. Conclusions Purtscher-like retinopathy may be linked to travel at high altitude through retinal vessel dilation and constriction leading to retinal vasospasm and precapillary arteriole occlusion. This proposed mechanism of pathogenesis suggests that Purtscher-like retinopathy may represent a partial central retinal artery occlusion.

Nitric oxide: what's new to NO?

Nitric oxide (NO) is one of the critical components of the vasculature, regulating key signaling pathways in health. In macrovessels, NO functions to suppress cell inflammation as well as adhesion. In this way, it inhibits thrombosis and promotes blood flow. It also functions to limit vessel constriction and vessel wall remodeling. In microvessels and particularly capillaries, NO, along with growth factors, is important in promoting new vessel formation, a process termed angiogenesis. With age and cardiovascular disease, animal and human studies confirm that NO is dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency. NO has also been implicated in diseases that are related to neurotransmission and cancer although it is likely that these processes involve NO at higher concentrations and from nonvascular cell sources. Conversely, NO and drugs that directly or indirectly increase NO signaling have found clinical applications in both age-related diseases and in younger individuals. This focused review considers recently reported advances being made in the field of NO signaling regulation at several levels including enzymatic production, receptor function, interacting partners, localization of signaling, matrix-cellular and cell-to-cell cross talk, as well as the possible impact these newly described mechanisms have on health and disease.

IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model

Coronary artery vasospasm (constriction) caused by reduced nitric oxide bioavailability leads to myocardial infarction. Reduced endothelial release of nitric oxide by the neurotransmitter acetylcholine, leads to paradoxical vasoconstriction as it binds to smooth muscle cell M3 receptors. Thus, inhibition of coronary artery vasospasm will improve clinical outcomes. Inhibition of insulin regulated aminopeptidase has been shown to improve vessel function, thus we tested the hypothesis that HFI419, an inhibitor of insulin regulated aminopeptidase, could reduce blood vessel constriction to acetylcholine. The abdominal aorta was excised from New Zealand white rabbits (n=15) and incubated with 3mM Hcy to induce vascular dysfunction in vitro for 1h. HFI419 was added 5min prior to assessment of vascular function by cumulative doses of acetylcholine. In some rings, vasoconstriction to acetylcholine was observed in aortic rings after pre-incubation with 3mM homocysteine. Incubation with HFI419 inhibited the vasoconstrictive response to acetylcholine, thus improving, but not normalizing, vascular function (11.5±8.9% relaxation vs 79.2±37% constriction, p<0.05). Similarly, in another group with mild vasoconstriction, HFI419 inhibited this effect (34.9±4.6% relaxation vs 11.1±5.2%, constriction, p<0.05). HFI419 had no effect on control aorta or aorta with mild aortic dysfunction. The present study shows that HFI419 prevents acetylcholine mediated vasoconstriction in dysfunctional blood vessels. HFI419 had no effect on normal vasodilation. Our results indicate a therapeutic potential of HFI419 in reducing coronary artery vasospasm.

Mixed vascular nevus syndrome: a report of four new cases and a literature review.

Mixed vascular nevus (or nevus vascularis mixtus) represents an admixture of cutaneous vascular malformations of the telangiectatic type and angiospastic spots of nevus anemicus. It can occur as an purely cutaneous trait or as a hallmark of a neurocutaneous phenotype (mixed vascular nevus syndrome) characterised by the combination of: (I) paired vascular (telangiectatic and anemic) twin nevi and brain abnormalities of the Dyke-Davidoff-Masson type (i.e., crossed cerebral/cerebellar hemiatrophy with hypoplasia of the ipsilateral cerebral vessels and homolateral hypertrophy of the skull and sinuses (hyperpneumatisation) with contralateral hemispheric hypertrophy); or (II) paired vascular twin nevi and brain malformations of the Dyke-Davidoff-Masson type in association with systemic abnormalities consisting in facial asymmetry, skeletal anomalies (i.e., Legg-Calvé-Perthes-like disease) and disorders of autoimmunity (i.e., diabetes, thyroiditis). In 2014, Happle proposed to name the syndrome with the eponym Ruggieri-Leech syndrome. Review of the existing literature on nevus vascularis mixtus and information on our personal experience on new cases and follow-up of previously reported cases by some of us. The existing literature revealed 4 previous studies including 33 cases with an inferred purely cutaneous trait and 3 cases with a combination of paired vascular twin nevi and brain malformation of the Dyke-Davidoff-Masson type. Our personal experience includes 4 unpublished patients (1 female and 3 males; currently aged 2 to 34 years) seen and followed-up at our Institutions in Italy who had: paired vascular nevi involving either the face (n=2) or the face and parts of the body (n=2); facial asymmetry (n=4); mild to moderate facial dysmorphic features (n=2); developmental delay (n=3); seizures/stroke-like episodes and associated hemiplegia (n=4); muscular hypotrophy (n=2); mild to moderate hemispheric atrophy (n=4); skull osseous hypertrophy (n=4); hyperpneumatisation of the sinuses (n=2); hypoplastic brain vessels (n=4); colpocephaly and malformation of cortical development (n=2). Follow-up data on our previous 2 cases revealed that the vascular abnormalities in the skin and nervous system were stable over years without neurological progression or deterioration. Pathogenically, this complex phenotype suggests that embryonic pairing and somatic recombination of recessive (didymotic) alleles controlling the balance between constriction (i.e., nevus anemicus) and dilatation (i.e., nevus telangiectaticus) of blood vessels could be the primary event causing the phenomena of cutaneous and brain vascular twin spotting and the paired phenomena of skull hyperpneumatisation vs. hypertrophy and brain megalencephaly/colpocephaly vs. cortical dysplasia. This association is likely more frequent than previously thought and should be investigated by means of: (I) brain and spinal cord imaging (combination of CT and MRI studies); (II) skeletal X-ray studies (when dictated by clinical findings); (III) systemic ultrasound studies; (IV) neurophysiologic studies (EEG); (V) psychomotor testing; (VI) and laboratory investigation (including immune-mediated dysfunction).

Endothelin-1 Treatment Induces an Experimental Cerebral Malaria–Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65

Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 106 PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations thatare the hallmark of ECM.

CLINICAL CHARACTERISTICS AND TREATMENT OUTCOME OF EPISTAXIS IN HEAD AND NECK TRAUMA

Objectives: To study clinical characteristics and treatment outcome of epistaxis in head and neck trauma. Methods: A prospective descriptive study of 71 cases of epistaxis managed at Hue Center Hospital and Hue Univesity Hospital from April 2015 to June 2016. Results: Most of bleeding times were at night (59.2%). Unilateral bleeding was seen in almost 72.9% cases. Anterior nasal bleeding was noted in majority of the patients (70.4%), anterior and posterior nasal was 18.3%, posterior nasal was 11.3%. There were three stage: mild (77.5%), moderate (15.5%), severe (7%). Anterior nasal packing (70.4%) were the most common methods, Posterior nasal packing were 25.4%, Local cauterization were 1.4%, Constriction of the blood vessels were 1.4%, Embolization procedure were 1.4%. Complication rate was 8.4% include: fever (5%), pressure necrosis (1.7%), scars (1.7%). The rate of good recovery after treatment was 91.7%, partial recovery was 8.3%. The overall mean of hospital stay was 6,33 ± 5,61 days (range 1 to 36 days). Key words: Epistaxis

Nucleolin Promotes Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis.

The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5' UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5'UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394-405. ©2016 AACR.

Abstract 3375: Activation of the acid sphingomyelinase pathway as a potential mechanism of chemotherapy-induced normal tissue vasculature damage

Abstract Background: Several classes of chemotherapy confer substantial risk for late-term vascular morbidity. We aimed to investigate the mechanisms of chemotherapy-induced vascular toxicity in normal tissues. Methods: The effect of Doxorubicin and Cisplatin has been studied in-vitro using bovine aortic endothelial cells (BAEC) as a model of normal tissue vascular endothelium. Specifically, we investigated activation of the acid sphingomyelinase (ASMase) pathway, which may lead to endothelial dysfunction (vasoconstriction) and apoptosis following incubation with different concentrations of Doxorubicin and Cisplatin. ASMase activity was measured using radioenzymatic assay with [N-methyl-14C] sphingomyelin. Cellular Reactive Oxygen Species (ROS) production was assessed using the 2’,7’-dichlorofluorescin diacetate (DCFDA) detection assay kit (Abcam®). Endothelial apoptosis was quantified using the 3,5-bis-benzamide assay (Sigma-Aldrich®). For the in-vivo studies, mouse femoral arterial blood flow was measured in real-time during and after Doxorubicin (8 mg/kg intravenously) or Cisplatin (8 mg/kg) administration. Visualization of ovarian and femoral microvasculature was obtained by fluorescence optical imaging system, equipped with a confocal fiber microscope (Cell-viZio). Results: Incubation of BAEC with Doxorubicin (0.25 μM or 0.50 μM) resulted in increased ASMase activity, production of ROS and induction of apoptosis in a dose-dependent fashion. Cisplatin (25 μM or 50 μM) generated significantly reduced effects in BAEC yet apoptosis and ROS were notable. In-vivo endoscopic fibered confocal microscopy following chemotherapy administration revealed a differential pattern between the two agents. While post Doxorubicin injection, there was a marked reduction in fluorescent signal in small vessels (&amp;lt;15 μM) indicating vessel constriction and disintegration of vessel's wall in larger vessels, Cisplatin treatment resulted in very minor vascular changes. Conclusions: These findings suggest that chemotherapy-induced vascular damage in normal tissues may represent different modes of toxicity in vivo and in vitro, while is mediated via activation of the ASMase pathway in response to Doxorubicin and to a lesser extent in response to Cisplatin. Citation Format: Aviram Mizrachi. Activation of the acid sphingomyelinase pathway as a potential mechanism of chemotherapy-induced normal tissue vasculature damage. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3375.

Variability of skin microcirculation in case of arterial hypertension from the view of distributional responses of blood flow

The aim of the study. To evaluate individual variability of skin microcirculation (MC) in patients with arterial hypertension (AH) and characteristics of microvascular (MV) reaction to hypotensive impact from the view of blood distribution. Material and methods. Microcirculation of forearm skin in 176 patients with AH stage 2 was studied by laser doppler flowmetry (LDF). All the patients were divided into 2 groups: 1 - with low (n=46) value of MV resistance and 2 - with high (n=130) value of MV resistance. 90 patients out of the total amount (also divided into the same 2 groups - 25 people in the first group and 65 people in the second) had another study of MC after sublingual taking of 20 mg of corinfar. Results. The results revealed controversial MC skin picture with high blood filling of MV canal and reduced MV tone in the first group and high value of MV tone with hemoperfusion limitation in the second group in patients with AH and the same blood pressure (BP). Reduction in the first group can be caused by redistribution of a minute blood volume kept on a high level in the condition of elevated total peripheral resistance (TPR) (the so called central blood bypass). In this case the skin where a part of a cardiac output goes to serves as a depot. Increase of intravascular resistance in the skin of patients from the second group is caused by prevalence of TPR in hemodynamic mechanisms of BP elevation. Whereas constriction of microcirculation vessel is observed not only in the abdominal vessel area (which is the main area responsible for TPR formation) but also in the other areas, particularly in the skin. Corresponding BP decrease in groups of patients under the influence of corinfar was accompanied by bidirectional shifts of MC values: vasodilation in the second group and vasoconstriction in the first group of patients. It happens due to more balanced bloodflow distribution in the vessel areas more responsible for TPR formation as a result of vasodilation under the influence of corinfar.

Faktor Dominan Risiko Terjadinya Penyakit Jantung Koroner (PJK)

Abstract: Risk Factors, CHD. Coronary Heart Disease (CHD) is the coronary atherosclerotic disease that causes narrowing of blood vessels. Constriction of blood vessels occurs because of atherosclerosis or spasm or a combination of both. the risk factors of CHD were divided into two, namely the factors that can not be changed and the factors can be changed. Factors that can not be changed include age, family history and gender. While the factors that can be changed include an increase in serum lipids (hyperlipidemia), personality type, smoking, impaired glucose tolerance (diabetes mellitus), lifestyle is less activity (physical inactivity), psychological stress, and hypertension. The purpose of this study to determine the risk factors that lead to increased incidence of coronary heart disease. The study is an observational analytic epidemiologic approach with cross sectional design with a sample of 40 respondents. The data analysis using logistic regression. The results showed the significant influence of CHD events by a factor of age&gt; 40 years (p = 0.7370, hyperlipidemia (p = 0162), hypertension (p = 0365), smoking (p = 0153), as well as physical inactivity (p = 0535 ). Smoking is a risk factor most dominant effect on the incidence of CHD with OR = 4,500. the case studies are necessary to further research with a number of larger samples and develop variable-varabel to be studied is associated with other behaviors and lifestyles that affect developing CHD.

Abstract 12: Nanotechnology-enabled Anti-mir-320 Therapy for Inhibiting Pathological Vasoconstriction

Subarachnoid hemorrhage (SAH) affects approximately 30,000 people each year and accounts for 1-7% of all strokes. Current SAH therapies globally affect blood pressure, potentially causing hypotension and reduced cranial perfusion. Alternatively, our approach is to locally reduce constriction of the blood vessels in the brain by targeting heat shock protein 20 (HSP 20) which plays a role in the thin filament pathway for contraction and relaxation. To this end, we developed nanoparticles for delivery of a locked nucleic acid (LNA, LNA-NPs) designed to inhibit miR-320, an endogenous negative regulator of HSP 20 expression in vascular tissue. We hypothesized that LNA-NP-enabled anti-miR-320 therapy would increase HSP 20 expression, reducing vessel contraction and increasing vessel relaxation. LNA-NPs were formulated with a PEGylated, endosomolytic polymer which has been previously optimized for systemic siRNA delivery (Fig. 1A). In this study, LNA-NPs efficiently complexed LNA (Fig. 1B) and formed ~100 nm diameter LNA-loaded nanoparticles (Fig. 1C). Efficient cytosolic delivery of LNA by LNA-NPs resulted in ~2.5-fold (n = 3, Fig. 1D) and 21% (n = 4, Fig. 1E) increased HSP 20 protein expression compared to LNA alone in rat aortic smooth muscle cells and rat aortic vessels, respectively. Functionally, LNA-NP treated tissue showed a 21% reduction in phenylephrine induced contraction relative to maximal 110 mM KCl-induced contraction (n = 4, Fig. 1F). Rat aorta treated with LNA-NPs also showed increased relaxation within the vessels to sodium nitroprusside by 8.1% (n=4, Fig. 1F). In sum, this approach allowed inhibition of miR-320 and direct modulation of HSP 20 in a translationally relevant organ culture model of vascular disease. Future studies will focus on inhibiting miR-320 in human saphenous vein ex vivo and in a pre-clinical model of SAH after systemic delivery.

Inhibition Of Inward‐Rectifier K+ Channels In Vascular Smooth Muscle Restores Myogenic Tone Development In Mouse Bladder Arterioles

The urinary bladder is highly vascularized, and chronic decreases in blood flow are linked to bladder dysfunction. While increases in intraluminal pressure constrict most arterioles (“myogenic tone”), mouse bladder arterioles do not exhibit a myogenic response to pressure. We examined the electrophysiological and vasoactive properties of mouse bladder feed arterioles to determine why myogenic tone is absent. In isolated pressurized bladder arterioles, smooth muscle cell membrane potential was hyperpolarized at 20 mmHg (−72.8±1.4 mV), and did not change significantly when intraluminal pressure was increased to 80 mmHg (−74.3±2.2 mV). However, increasing extracellular K+ from 5.9 mM to 60 mM caused a significant depolarization (−22.7±0.2 mV) at 80 mmHg, which was accompanied by vessel constriction. Given that inward‐rectifier K+ (KIR) channels can have a strong influence on membrane potential in smooth muscle cells, membrane potential was again measured in the presence or absence of the KIR channel blocker BaCl2 (100 μM). In the absence of BaCl2, smooth muscle cell membrane potential remained hyperpolarized at both 20 to 80 mmHg (−70.4±1.9 mV and −72.2±3.1 mV, respectively). In the presence of BaCl2, membrane potential depolarized significantly at both 20 mmHg (−56.2±3.1 mV) and 80 mmHg (−43.3±2.0 mV). To determine if KIR channel inhibition could restore myogenic tone, diameter of isolated pressurized bladder arterioles was measured at increasing pressures (10–80 mmHg) in the presence and absence of 100 μM BaCl2. BaCl2 had no effect on vessel diameter at 20 and 40 mmHg, but resulted in the development of significant myogenic tone at both 60 and 80 mmHg (25.5±9.1% and 41.5±3.9% constriction, respectively). These data support the concept that, in urinary bladder arterioles, KIR channel conductance cannot be overcome by pressure‐induced depolarizing conductances, and thus smooth muscle cell membrane potential remains hyperpolarized and the arterioles do not constrict as intraluminal pressure increases. This represents a novel adaptation to maintain blood flow into the bladder during filling.Support or Funding InformationSupported by NIH R37DK053832 and K01DK103840.