Vasculature Of Rats Research Articles

Effect of Bushen Yiqi Huoxue recipe on placental vasculature in pregnant rats with fetal growth restriction induced by passive smoking

Interactions of vascular endothelial growth factor (VEGF) with receptors VEGFR1/Flt1 and VEGFR2/Flk1, and those of angiopoietins (Ang-1, Ang-2) with receptor Tie2 play important roles in placental angiogenesis. This study investigated vascular morphology and expression of these angiogenic factors in rat placenta on the day 15, 18, 21 of gestation (D15, D18 and D21). The rats were randomly assigned into 3 groups: normal group, model group [fetal growth restriction (FGR) model], and Bushen Yiqi Huoxue (BYHR) recipe treatment group (BYHR group, the pregnant rats with FGR were treated with BYHR recipe). Morphological analysis indicated that during initial villous formation, fetal nucleated erythrocytes (FNEs) appeared in maternal blood sinus (MBS). Subsequently, FNEs were surrounded by endothelial cells to form fetal capillary (FC) and then by trophoblast cells to form villi. As pregnancy proceeded, FC density increased progressively with increasing endothelial identification staining (EIS) in normal and BYHR groups. Whereas, villous formation was suppressed, normal increase in FC density was impaired and EIS was weakened in model group. Quantitative PCR analysis showed that VEGF and Flk1 mRNA increased over gestation in all groups, indicating that VEGF might play a pivotal role in FC growth during late gestation. VEGF mRNA was increased on D15, while decreased on D21 in model group as compared with normal group and BYHR group. Immunohistochemically, Ang-2 protein was highly expressed in FNEs, gradually disappeared as villi matured, and decreased over gestation in all groups, indicating that Ang-2 might play a pivotal role in villous formation, which was further supported by decreased Ang-2 mRNA and protein expression in model group on D15. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio increased from D15 to D18 in all groups as placenta matured. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio were decreased on D18 in model group as compared with normal and BYHR groups, indicating delayed maturity of FGR placenta. Alterations in angiogenic factors may result in altered placental vasculature and cause placental insufficiency. BYHR recipe could balance the angiogenic factors to promote the formation and maturation of FGR placental vasculature.

Cerebral Neovascularization and Remodeling Patterns in Two Different Models of Type 2 Diabetes

We previously reported intense pial cerebral collateralization and arteriogenesis in a mild and lean model of type 2 diabetes (T2D), Goto-Kakizaki (GK) rats. Increased cerebral neovascularization differed regionally and was associated with poor vessel wall maturity. Building upon these findings, the goals of this study were to determine whether a) glycemic control prevents this erratic cerebral neovascularization in the GK model, and b) this pathological neovascularization pattern occurs in Leprdb/db model, which is the most commonly used model of T2D for studies involving cerebral complications of diabetes. Vascular volume, surface area and structural parameters including microvessel/macrovessel ratio, non-FITC (fluorescein) perfusing vessel abundance, vessel tortuosity, and branch density were measured by 3D reconstruction of FITC stained vasculature in GK rats or Leprdb/db mice. GK rats exhibited an increase in all of these parameters, which were prevented by glycemic control with metformin. In Leprdb/db mice, microvascular density was increased but there was no change in nonFITC-perfusing vessels. Increased PA branch density was associated with reduced branch diameter. These results suggest that T2D leads to cerebral neovascularization and remodeling but some structural characteristics of newly formed vessels differ between these models of T2D. The prevention of dysfunctional cerebral neovascularization by early glucose control suggests that hyperglycemia is a mediator of this response.

Role of impaired endothelial cell Ca2+signaling in uteroplacental vascular dysfunction during diabetic rat pregnancy

Diabetes mellitus in pregnancy is associated with impaired endothelium-mediated dilatation of maternal arteries, although the underlying cellular mechanisms remain unknown. In this study, we hypothesized that diabetes during rat gestation attenuates agonist-induced uterine vasodilation through reduced endothelial cell (EC) Ca(2+) elevations and impaired smooth muscle cell (SMC) hyperpolarization and SMC intracellular Ca(2+) concentration ([Ca(2+)]i) responses. Diabetes was induced by an injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with a citrate buffer. Fura-2-based measurements of SMC [Ca(2+)]i or microelectrode recordings of SMC membrane potential were performed concurrently with dilator responses to ACh in uteroplacental arteries from control and diabetic pregnant rats. Basal levels of EC [Ca(2+)]i and ACh-induced EC [Ca(2+)]i elevations in pressurized vessels and small EC sheets were studied as well. Diabetes reduced ACh-induced vasodilation due to a markedly impaired EDHF-mediated response. Diminished vasodilation to ACh was associated with attenuated SMC hyperpolarization and [Ca(2+)]i responses. Basal levels of EC [Ca(2+)]i and ACh-induced EC [Ca(2+)]i elevations were significantly reduced by diabetes. In conclusion, these data demonstrate that reduced endothelium-mediated hyperpolarization contributes to attenuated uteroplacental vasodilation and SMC [Ca(2+)]i responses to ACh in diabetic pregnancy. Impaired endothelial Ca(2+) signaling is in part responsible for endothelial dysfunction in the uterine resistance vasculature of diabetic rats. Pharmacological improvement of EC Ca(2+) handling may provide an important strategy for the restoration of endothelial function and enhancement of maternal blood flow in human pregnancies complicated by diabetes.

Chronological changes in renal vascular reactivity in portal hypertensive rats

Circulatory dysfunction in portal hypertension is characterized by increased cardiac output, decreased systemic vascular resistance, a fall in mean arterial pressure secondary to splanchnic and systemic vasodilation and hence renal hypoperfusion. Previous studies have disclosed that renal vasculatures of portal hypertensive rats had lower perfusion pressure and hyporesponsiveness to endogenous vasoconstrictors. However, the sequences of altered renal haemodynamics have never been described. This study aimed to explore the evolution of renal vascular hyporeactivity and associated mechanisms during portal hypertension. All rats were randomized into partial portal vein ligation (PVL) or shamed surgery. Isolated kidney perfusion was performed at postoperative day 1, 4, 7 and 14, respectively, to evaluate chronologically renal vascular response to endothelin-1. Renal arteries and kidneys were harvested for further analysis. Impaired renal vascular reactivity to endothelin-1 developed 1 week following PVL. There were extensive up-regulations of vasodilative nitric oxide synthase (NOS) and cyclooxygenase-2 in renal arteries of PVL rats. Among them, the changes in endothelial NOS paralleled with the evolution of renal vascular hyporesponsiveness. Preincubation of NOS inhibitor attenuated the renal vascular hyporeactivity in PVL rats. Up-regulated NOS and down-regulated cyclooxygenase-2 in kidneys of PVL rats might play a critical role to maintain renal circulation and body fluid homoeostasis in response to systemic hypotension. This investigation highlights the versatile nature of renal vasculatures in portal hypertension, which is replete with compensatory mechanisms. It may help to unveil potential mechanisms of severe renal dysfunction in advanced liver disease.

Bilateral internal carotid arteries ligation temporary impairs brain vasculaturev in young rats

Bilateral internal carotid artery ligation (BICL) rat model is one of the chronic cerebral hypoperfusion animal models used for investigating brain dysfunction related diseases. Cerebral blood flow decreases in different cerebral regions in a time-dependent manner after the BICL. However little is known about the cerebral vasculature change in the brain after the BICL. In the current study, the bilateral internal carotid arteries of the juvenile rats were permanently ligated and the change of the cerebral vasculature was studied 7, 14 and 21 days after the BICL. In the juvenile rats, 7 days after the BICL, the functional vascular area was decreased significantly in the anterior half of the cerebral cortex, but it had only little decrease in the posterior half of the cerebral cortex and hippocampus. However, at the time points of 14 and 21 days after the surgery, the functional vascular area throughout the whole cerebral cortex and hippocampus was almost similar to those in the sham control rats. In conclusion, the results from our current study showed that in the BICL hypoperfusion model in young rats, the brain functional vascular area was impaired initially in certain brain regions after the artery ligation, but likely to be quickly self-recovered late after. The results suggest that the brain vasculature in young rats has plasticity to external insult caused by cerebral hypoperfusion.

Cell–Cell Communication in the Kidney Microcirculation

In the renal vasculature of humans, rats, and mice, at least four isoforms of Cx, Cxs 37, 40, 43, and 45 are expressed. In the ECs, Cx40 is the predominantly expressed Cx, whereas Cx45 is suggested to be expressed in the VSMCs. The preglomerular vasculature has a higher expression of Cxs than the postglomerular vasculature. Cxs form gap junctions between neighboring cells, and as in other organ systems, the major function of Cxs in the kidney appears to be mediation of intercellular communication. Cxs may also form hemichannels that allow cellular secretion of signaling molecules like ATP, and thereby mediate paracrine signaling. Renal Cxs facilitate vascular conduction, juxtaglomerlar apparatus calcium signaling, and enable ECs and VSMCs to communicate. Thus, current research suggests multiple roles for Cxs in important regulatory mechanisms within the kidney, including the renin-angiotensin system, TGF, and salt and water homeostasis. Interestingly, changes in the activity of the renin-angiotensin system or changes in blood pressure seem to affect the expression of the renal vascular Cxs. At the systemic level, renal Cxs may be involved in blood pressure regulation, and possibly in the pathogenesis of hypertension and diabetes.

Prevention and management of diabetic retinopathy in STZ diabetic rats by Tinospora cordifolia and its molecular mechanisms

We investigated the potential of Tinospora cordifolia (TC) in treatment of diabetic retinopathy in STZ-induced rats due to its antihyperglycemic, angiogenic, antiinflammatory and antioxidant effects. The diabetic rats, treated for 24weeks with TC extract (250mg/kg), were evaluated for lenticular and fundus changes. Biochemical parameters were estimated and histopathological studies performed. TC significantly reduced blood glucose and glycated hemoglobin in treated rats. It prevented cataract development in treated group. Angiogenic markers VEGF and PKC increased in diabetic retina, which reduced significantly with TC. Anti-inflammatory parameters TNF-α and IL-1β elevated in diabetic group unlike that in treated group. TC also provided defense against depletion of antioxidant enzymes- glutathione and catalase. Histopathological studies revealed thickening of basement membrane of the retinal and glomerular vasculature of diabetic rat, but no basement membrane widening was seen in treated animals. Destruction of pancreatic islet structure was observed in diabetic group, but not in treated. Thus, TC reduces blood glucose and inhibits overexpression of angiogenic and inflammatory mediators, which are distinct markers of diabetic retinopathy. It also prevents retinal oxidative stress and restores antioxidant enzyme levels. These data provide evidence for the safety and potential effect of TC in the management of experimental diabetic retinopathy.

The effects of high and low intensity exercise on heat shock protein accumulation in rat skeletal muscle and vasculature

Exercise is a stressor that activates cytoprotective heat shock proteins (Hsps) in skeletal muscle (SM). Though exercise intensity influences this response, the localization of Hsps to skeletal myofibers versus the vasculature following various exercise loads has yet to be examined. The hypothesis tested was that induction of Hsp70 and 90 in skeletal muscle and blood vessels (BVs) is intensity‐dependent, with greater increases following high‐intensity (HIEX) than low‐intensity exercise (LOEX). Rats (n=10 per group) were sacrificed 24hr after a single exercise bout of 1hr treadmill running (2%incline) at either LOEX (15m/min) or HIEX (30m/min). A control group (CON) was similarly handled yet underwent no exercise. Immunofluorescent localization of Hsp70 and 90 was conducted on the white portion of the vastus muscle (WV). Hsp70 positive fibres were absent in WV of both CON and LOEX but found in HIEX (~5% of all fibres). Hsp70 was not detected in CON BV, was observed mainly in large BV's in LOEX and had a greater distribution to most BV's of HIEX. Hsp90 was equally robust in larger BVs in both HI and LOEX and greater than in CON. These observations confirm that in skeletal myofibers and vasculature Hsp70 is induced post exercise and exercise intensity determines the extent and localization of the response. Hsp90 is found solely in the vasculature and is elevated by exercise independent of intensity.

Enhanced endothelin‐1 response in mesenteric arteries in acquired and inherited forms of hypertension

Both endothelin and the ET‐1 receptor are altered in ouabain sensitive and hypertensive (mRen‐2)27 transgenic rats, consistent with the lowering of blood pressure in both models of hypertension with either AT1 or ET‐1 receptor blockade. We hypothesized that responses to ET‐1 receptor activation are enhanced in the vasculature of the animals with acquired and genetic hypertension. Sprague‐Dawley rats were implanted subcutaneously with a 60‐ day 1.5 mg ouabain (OUA) pellet (n = 6 control, n = 6 treated). Blood pressure (BP) was recorded daily via tail cuff for 8 weeks. Transgenic hypertensive (mRen‐2)27 rats (n = 6) were also used. Third branch mesenteric arteries were mounted in a wire myograph (DMT‐USA). Maximal responses to KCl and ET‐1 were expressed as KMAX (mN/mm) and ET‐1MAX (% KMAX) and sensitivity as pD2 (pD2=‐Log[EC50]). Pre‐incubation with indomethacin (10−5M) or LNAME (10−4M) were performed in parallel. OUA increased systolic BP by 30% (p<0.05) whereas age‐matched (mRen‐2)27 rats had a 55% higher BP vs control (p<0.05). ET‐1MAX was similar in the three groups [ET‐1MAX (mRen‐2)27 136 ± 5%; OUA 128 ± 14% vs control 137 ± 8 % KMAX]. However sensitivity to ET‐1 was increased in hypertensive vs control rat vasculature [(mRen‐2)27 8.6 ± 0.1; OUA 8.5 ± 0.2 vs control 8 ± 0.1, p<0.05]. A greater sensitivity to ET‐1 may serve as mediator of enhanced vascular tone in both models of hypertension.Supported by NIMHD MD002303

Interplay of macrophages and T cells in the lung vasculature

In severe pulmonary arterial hypertension (PAH), vascular lesions are composed of phenotypically altered vascular and inflammatory cells that form clusters or tumorlets. Because macrophages are found in increased numbers in intravascular and perivascular space in human PAH, here we address the question whether macrophages play a role in pulmonary vascular remodeling and whether accumulation of macrophages in the lung vasculature could be compromised by the immune system. We used the mouse macrophage cell line RAW 264.7 because these cells are resistant to apoptosis, have high proliferative capacity, and resemble cells in the plexiform lesions that tend to pile up instead of maintaining a monolayer. Cells were characterized by immunocytochemistry with cell surface markers (Lycopersicon Esculentum Lectin, CD117, CD133, FVIII, CD31, VEGFR-2, and S100). Activated, but not quiescent, T cells were able to suppress RAW 264.7 cell proliferative and migration activity in vitro. The carboxyfluorescein diacetate-labeled RAW 264.7 cells were injected into the naïve Sprague Dawley (SD) rat and athymic nude rat. Twelve days later, cells were found in the lung vasculature of athymic nude rats that lack functional T cells, contributing to vascular remodeling. No labeled RAW 264.7 cells were detected in the lungs of immune-competent SD rats. Our data demonstrate that T cells can inhibit in vitro migration and in vivo accumulation of macrophage-like cells.

Phytoestrogens Enhance the Vascular Actions of the Endocannabinoid Anandamide in Mesenteric Beds of Female Rats

In rat isolated mesenteric beds that were contracted with NA as an in vitro model of the vascular adrenergic hyperactivity that usually precedes the onset of primary hypertension, the oral administration (3 daily doses) of either 10 mg/kg genistein or 20 mg/kg daidzein potentiated the anandamide-induced reduction of contractility to NA in female but not in male rats. Oral treatment with phytoestrogens also restored the vascular effects of anandamide as well as the mesenteric content of calcitonin gene-related peptide (CGRP) that were reduced after ovariectomy. The enhancement of anandamide effects caused by phytoestrogens was prevented by the concomitant administration of the estrogen receptor antagonist fulvestrant (2.5 mg/kg, s.c., 3 daily doses). It is concluded that, in the vasculature of female rats, phytoestrogens produced an estrogen-receptor-dependent enhancement of the anandamide-vascular actions that involves the modulation of CGRP levels and appears to be relevant whenever an adrenergic hyperactivity occurs.

Uterine distension differentially affects remodelling and distensibility of the uterine vasculature in non-pregnant rats

During pregnancy the mammalian uterine circulation undergoes significant expansive remodelling necessary for normal pregnancy outcome. The underlying mechanisms are poorly defined. The goal of this study was to test the hypothesis that myometrial stretch actively stimulates uterine vascular remodelling by developing a new surgical approach to induce unilateral uterine distension in non-pregnant rats. Three weeks after surgery, which consisted of an infusion of medical-grade silicone into the uterine lumen, main and mesometrial uterine artery and vein length, diameter and distensibility were recorded. Radial artery diameter, distensibility and vascular smooth muscle mitotic rate (Ki67 staining) were also measured. Unilateral uterine distension resulted in significant increases in the length of main uterine artery and vein and mesometrial segments but had no effect on vessel diameter or distensibility. In contrast, there were significant increases in the diameter of the radial arteries associated with the distended uterus. These changes were accompanied by reduced arterial distensibility and increased vascular muscle hyperplasia. In summary, this is the first report to show that myometrial stretch is a sufficient stimulus to induce significant remodelling of uterine vessels in non-pregnant rats. Moreover, the results indicate differential regulation of these growth processes as a function of vessel size and type.

Vascular Remodeling in Hypertension

Over the past few years noninvasive and invasive techniques have allowed a better appreciation of vascular changes in hypertensive humans and experimental animals.1 Large arteries undergo outward hypertrophic remodeling and increased stiffness with aging,2–4 and in hypertension there may be an acceleration of this process leading to enhanced pulse pressure. A reduced aortic diameter in middle-aged hypertensive subjects may also play a role in increases in pulse pressure through increased specific impedance,5 contradicting the classic hypertensive aortic phenotype characterized by vascular wall degeneration and calcification and increased aortic diameter. In advanced hypertension, however, the elastic laminae undergo duplication and fragmentation, with increased deposition of collagen and fetal (EIIIA) fibronectin, contributing to increased stiffness. Classically the remodeling of small arteries in hypertension has been associated with increased media thickness, but recent studies have demonstrated that 2 types of remodeling are found, inward eutrophic or inward hypertrophic remodeling, depending on whether the media cross-sectional area is enlarged (true hypertrophy).6–9 Although eutrophic remodeling is usually found in essential (primary) hypertension in humans and spontaneously hypertensive rats (SHRs); in secondary hypertension such as in renovascular hypertension, primary aldosteronism, or in pheochromocytoma10; in hypertension associated with diabetes mellitus11,12; and in acromegaly,13 hypertrophic remodeling has been described. In mineralocorticoid hypertension in rodents14,15 and in salt-sensitive Dahl rats,16 in both of which the endothelin (ET) system is activated, remodeling of small arteries is also hypertrophic (see below). Thus, when the renin-angiotensin system is even mildly activated (primary hypertension and SHRs), remodeling is usually eutrophic. In salt-dependent hypertension, diabetes mellitus, and malignant hypertension, all conditions in which the ET system is activated, remodeling is hypertrophic.17 Hyperplasia of vascular smooth muscle cells (VSMCs) is found in small arteries of …

Changes of the vasculature and innervation in the anterior segment of the RCS rat eye

Investigating the anterior eye segment vasculature and innervation of dystrophic RCS rats, two major unique findings were observed: in the iris, young adult animals with retinal dystrophy showed an increase in substance P nerve fibres and a dilation of arterioles and capillaries. This finding continued during ageing. In the pars plana region, the surface covered by venules decreased continuously with age. In older animals, this decrease was parallelled by a local decrease of sympathetic TH-positive nerve fibres supplying these venules. For both conditions, no comparable data exists so far in the literature. They might point to a unique situation in the anterior eye segment of the dystrophic RCS rat.

STIM1/Orai1 contributes to sex differences in vascular responses to calcium in spontaneously hypertensive rats

Sex differences in Ca2+-dependent signalling and homoeostasis in the vasculature of hypertensive rats are well characterized. However, sex-related differences in SOCE (store-operated Ca2+ entry) have been minimally investigated. We hypothesized that vascular protection in females, compared with males, reflects decreased Ca2+ mobilization due to diminished activation of Orai1/STIM1 (stromal interaction molecule 1). In addition, we investigated whether ovariectomy in females affects the activation of the Orai1/STIM1 pathway. Endothelium-denuded aortic rings from male and female SHRSP (stroke-prone spontaneously hypertensive rats) and WKY (Wistar-Kyoto) rats and from OVX (ovariectomized) or sham female SHRSP and WKY rats were used to functionally evaluate Ca2+ influx-induced contractions. Compared with females, aorta from male SHRSP displayed: (i) increased contraction during the Ca2+-loading period; (ii) similar transient contraction during Ca2+ release from the intracellular stores; (iii) increased activation of STIM1 and Orai1, as shown by the blockade of STIM1 and Orai1 with neutralizing antibodies, which reversed the sex differences in contraction during the Ca2+-loading period; and (iv) increased expression of STIM1 and Orai1. Additionally, we found that aortas from OVX-SHRSP showed increased contraction during the Ca2+-loading period and increased Orai1 expression, but no changes in the SR (sarcoplasmic reticulum)-buffering capacity or STIM1 expression. These findings suggest that augmented activation of STIM1/Orai1 in aortas from male SHRSP represents a mechanism that contributes to sex-related impaired control of intracellular Ca2+ levels. Furthermore, female sex hormones may negatively modulate the STIM/Orai1 pathway, contributing to vascular protection observed in female rats.

Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension

We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.

A novel vascular EET synthase: role of CYP2C7

We demonstrated previously that cytochrome P-450 (CYP) 2C29 is the epoxyeicosatrienoic acid (EET) synthase responsible for the EET-mediated flow/shear stress-induced dilation of vessels of female nitric oxide (NO)-deficient mice (Sun D, Yang YM, Jiang H, Wu H, Ojami C, Kaley G, Huang A. Am J Physiol Regul Integr Comp Physiol 298: R862-R869, 2010). In the present study, we aimed to identify which specific CYP isoform(s) is the source of the synthesis and release of EETs in response to stimulation by shear stress in vessels of rats. Cannulated mesenteric arteries isolated from both sexes of N(G)-nitro-L-arginine methyl ester (L-NAME)-treated rats were perfused with 2 and 10 dyn/cm(2) shear stress, followed by collection of the perfusate to determine EET concentrations and isoforms. Shear stress stimulated release of EETs in the perfusate of female (but not male) NO-deficient vessels, associated with an EET-mediated vasodilation, in which 11,12- and 14,15-EET contributed predominantly to the responses. Rat CYP cDNA array screened a total of 32 CYP genes of mesenteric arteries, indicating a significant upregulation of CYP2C7 in female L-NAME-treated rats. Endothelial RNA and protein were extracted from intact single vessels. Expression of CYP2C7 mRNA and protein in pooled extractions of endothelial lysate was identified by PCR and Western blot analyses. Transfection of the vessels with CYP2C7 short interfering RNA eliminated the release of EETs, consequently abolishing the EET-mediated flow-induced dilation; these responses, however, were maintained in vessels transfected with nonsilencing short interfering RNA. Knockdown of endothelial CYP2C7 was confirmed by PCR and Western blot analyses. In conclusion, CYP2C7 is an endothelial EET synthase in the female rat vasculature, by which, in NO deficiency, shear stress stimulates the release of EETs to initiate vasodilation.

Pharmacological and expression profile of the prostaglandin I 2 receptor in the rat craniovascular system

Activation of the trigeminal nerve terminals around cerebral and meningeal arteries is thought to be an important patho-mechanism in migraine. Vasodilatation of the cranial arteries may also play a role in increasing nociception. Prostaglandin I 2 (PGI 2) is capable of inducing a headache in healthy volunteers, a response that is likely to be mediated by the prostaglandin I 2 receptor (IP). This study investigates the functional and molecular characteristics of the IP receptor in the rat craniovascular system. In the closed cranial window model, iloprost, an IP receptor agonist, dilated the rat middle meningeal artery (MMA) (E max = 170% ± 16%; pED 50 = 6.5 ± 0.2) but not the rat cerebral artery (CA) in vivo. The specific antagonist of the IP receptor, CAY10441, significantly blocked the iloprost-induced response dose-dependently, with the highest dose attenuating iloprost (1 μg kg − 1 ) induced dilatations by 70% ( p < 0.05). CAY10441 did not have any effect on the prostaglandin E 2-induced vasodilatory response, thus suggesting no interaction with EP 2 and EP 4 receptors. IP receptor mRNA transcripts and protein were present in meningeal as well as in cerebral rat vasculature, and localized the IP receptor protein to the smooth vasculature of the cranial arteries (MMA, MCA and basilar artery). Together, these results demonstrate that the IP receptor mediates the dilatory effect of PGI 2 in the cranial vasculature in rats. Antagonism of this receptor might be of therapeutic relevance in acute migraine treatment.

High-fructose feeding impacts on the adrenergic control of renal haemodynamics in the rat

The present study explored the hypothesis that a prolonged 8 weeks exposure to a high fructose intake suppresses adrenergic and angiotensin II (Ang II)-mediated vasoconstriction and is associated with a higher contribution of α1D-adrenoceptors. A total of thirty-two Sprague-Dawley rats received either 20% fructose solution (FFR) or tap water (control, C) to drink ad libitum for 8 weeks. Metabolic and haemodynamic parameters were assessed weekly. The renal cortical vasoconstrictor responses to noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined in the presence and absence of BMY7378 (α1D-adrenoceptor antagonist). FFR had increased blood pressure, plasma levels of glucose, TAG and insulin. FFR expressed reduced renal vascular responses to adrenergic agonists and Ang II (NA: 50%, PE: 50%, ME, 65%, Ang II: 54%). Furthermore in the C group, the magnitude of the renal cortical vasoconstriction to all agonists was blunted in the presence of the low or high dose of BMY7378 (NA: 30 and 31%, PE: 23 and 33%, ME: 19 and 44%, Ang II: 53 and 77%), respectively, while in the FFR, vasoconstriction was enhanced to adrenergic agonists and reduced to Ang II (NA: 8 and 83%, PE: 55%, ME, 2 and 177%, Ang II: 61 and 31%). Chronic high fructose intake blunts vascular sensitivity to adrenergic agonists and Ang II. Moreover, blocking of the α1D-adrenoceptor subtype results in enhancement of renal vasoconstriction to adrenergic agonists, suggesting an inhibitory action of α1D-adrenoceptors in the FFR. α1D-Adrenoceptors buffer the AT1-receptor response in the renal vasculature of normal rats and fructose feeding suppressed this interaction.

Comparison of the function of the serotonin transporter in the vasculature of male and female rats

1. The serotonin transporter (SERT) handles serotonin (5-hydroxytryptamine (5-HT)) and is blocked by the antidepressant SERT inhibitors fluoxetine and fluvoxamine. Although the importance of SERT in the central nervous system is clear, SERT also functions in the peripheral vasculature. In the present study, we tested the hypothesis that the vasculature from female rats has increased SERT function compared with male rats because females are more responsive to SERT inhibitors. 2. In addition to in vitro experiments, in vivo experiments were used to evaluate how male and female rats handle chronically elevated levels of 5-HT. Wild-type (WT) and SERT-knockout (SERT-KO) rats were infused with 5-HT (25 μg/kg per min) for 7 days by minipump. 3. Using HPLC analysis, we demonstrated that blood vessels (aorta, carotid artery, jugular vein and vena cava) from naïve, non-infused female rats took up 5-HT acutely in vitro in a SERT-dependent manner. In in vitro experiments, SERT affected the contractility of aortas from female rats, as evidenced by an eightfold increase in potency of 5-HT in fluvoxamine (1 μmol/L)-incubated WT aortas compared with control. Fluvoxamine did not alter 5-HT-induced contraction in aortas from SERT-KO female rats. 4. Infusion of 5-HT resulted in an increase in tissue 5-HT that was reduced to a larger extent in blood vessels from female than male SERT-KO rats. Aortic contractions to 5-HT were abolished in aortas from male and female 5-HT-infused SERT-KO rats compared with WT rats. 5. Collectively, these data suggest that SERT function, when challenged with 5-HT, is modestly more important in the vasculature of the female compared with male rat.