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PubMed1998

Intima-adventitia apposition in end-to-side arterial anastomosis: an experimental study in the pig.

BACKGROUND: To prevent ischemic complications during coronary bypass grafting on the beating heart, a nonocclusive distal anastomosis technique is needed. One recently developed nonocclusive technique requires apposition of the intima of the graft to the adventitia of the recipient artery, in contrast to current surgical practice, which dictates apposition of both intimas. METHODS: To compare the sole effect of intima-adventitia apposition (n = 18) versus traditional intima-intima apposition (n = 18), we investigated radiolabeled platelet deposition and histomorphologic aspects of vascular wall healing quantitatively in a porcine carotid artery bypass graft model. Both groups were evaluated at 2 hours, 2 days, or 4 weeks. RESULTS: Within the first 2 hours, 3 of 6 pigs with intima-adventitia apposition exhibited cyclic flow reductions as a result of massive mural thrombosis. After intima-adventitia apposition, the number of deposited platelets was significantly higher compared with intima-intima apposition, 147.1 +/- 73.0 x 10(6) and 4.6 +/- 1.0 x 10(6) platelets/cm2 (mean +/- standard error of the mean), respectively (p = 0.03). At 2 days, the suture line was covered with small mural thrombi, whereas no thrombi were found after intima-intima apposition. At 4 weeks, intimal hyperplasia at heel and toe was not significantly different from that with intima-intima apposition. CONCLUSIONS: Despite thrombotic phenomena in the early phase, intima-adventitia apposition yielded a patent anastomosis with a small intimal hyperplasia response.

Anastomosis, Surgical↗
PubMed1999

Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery.

BACKGROUND: Histamine, a product of mast cells, is an effective vasoconstrictor of atherosclerotic coronary arteries. Because it has been suggested that coronary spasm plays a role in acute coronary syndromes such as myocardial infarction (MI), we quantified and characterized the mast cells in the adventitia of infarct-related coronary arteries. METHODS AND RESULTS: In a series of 17 autopsied MI patients, we identified the segment of the left coronary artery with ruptured plaque responsible for the infarction. More distal segments from the infarct-related coronary artery, either with nonruptured plaques or with normal intima, were also studied. Corresponding segments taken from left coronary arteries obtained from 17 patients who had died of noncardiac causes served as controls. Adventitial mast cells in the infarct-related and the control coronary arteries were identified immunohistochemically by staining for tryptase. In the infarct-related coronary arteries, we also stained for chymase and histamine. Moreover, T lymphocytes and macrophages were identified immunohistochemically and counted. In the infarct-related coronary arteries, significantly larger numbers of mast cells were present in the adventitia backing ruptured plaques (98+/-40 mast cells/mm2, mean+/-SD) than in the adventitia backing nonruptured plaques (41+/-12 mast cells/mm2; P<0.001) or backing normal intima (19+/-8 mast cells/mm2; P<0.001). No such difference was found among the 3 different segments in the control coronary arteries. The majority of mast cells contained not only tryptase but also chymase. Mast cells were the only cells in the coronary adventitia that contained histamine. The proportion of adventitial mast cells that were degranulated was highest in the segments with ruptured plaques. The numbers of adventitial macrophages and T lymphocytes were also increased in the segments with plaque rupture. CONCLUSIONS: In infarct-related coronary arteries, the number of degranulated mast cells in the adventitia backing ruptured plaques is increased. Histamine released from the degranulated mast cells may reach the media, where it may locally provoke coronary spasm and thus contribute to the onset of MI.

Aged↗
PubMed1996

Presence of angiotensin II AT2 receptor binding sites in the adventitia of human kidney vasculature.

1. Angiotensin II (AngII) receptor subtypes in adult human kidney were pharmacologically characterized by in vitro autoradiography using the AngII receptor subtype-selective antagonists, losartan and PD 123319, and the sensitivity to the reducing agent, dithiothreitol. 2. High densities of AngII AT1 receptor binding occur in the glomeruli and the inner stripe of the outer medulla, while a moderate AT1 receptor binding is localized in the proximal convoluted tubules. 3. AT2 receptor binding is observed predominantly in the intrarenal large blood vessels, including the arcuate, inter- and intra-lobular arteries, and in the renal capsule. 4. In the major renal artery, AT1 receptor binding is abundant in the media and adventitia, while AT2 receptor binding is observed mainly in the adventitia. 5. At the light microscopic level using emulsion autoradiography, AT1 receptors are localized in the glomeruli and juxtaglomerular apparatus, as expected. However, in larger renal blood vessels, including the arcuate arteries, inter- and intra-lobular arteries, intense AT2 receptor labelling occurs primarily in the adventitia, while the endothelium and vascular smooth muscle layers contain only low levels of AngII receptor binding. 6. These results indicate that the adult human kidney displays two pharmacologically distinct AngII receptor subtypes, with AT1 predominating in the glomeruli, juxtaglomerular apparatus, proximal tubules and the inner stripe of the outer medulla, while AT2 predominates in the adventitia of the arcuate and interlobular arteries and the renal capsule. The functional significance of AT2 receptor binding sites in the adventitia of adult human kidney vessels remains to be elucidated.

Adult↗
PubMed1997

Perindopril chronically inhibits angiotensin-converting enzyme in both the endothelium and adventitia of the internal mammary artery in patients with ischemic heart disease.

BACKGROUND: ACE inhibitors are widely used in treating hypertension and heart failure, but the sites and mechanisms of ACE inhibition in human blood vessels are not understood. The present study was undertaken to assess the sites and extent of in vivo inhibition of ACE by long-term perindopril treatment in different layers of the internal mammary artery in patients with ischemic heart disease. METHODS AND RESULTS: Sixteen patients with ischemic heart disease were treated either with perindopril (4 mg/d PO) for up to 36 days before surgery (n = 9) or without the inhibitor as control subjects (n = 7). The segments of the internal mammary artery were collected for measurement of vascular free and total ACE by quantitative in vitro autoradiography with 125I-351A binding. The patients treated with perindopril had lower plasma ACE (P < .001) and plasma angiotensin (Ang) II-to-Ang I ratio (P < .05). In the internal mammary artery, free ACE was similarly inhibited by perindopril in the endothelium (P < .05) and adventitia (P < .05), and the free ACE-to-total ACE ratio, an index of ACE inhibition, was markedly decreased by perindopril in parallel in the endothelium (P < .001) and adventitia (P < .001). Moreover, plasma ACE correlated highly with vascular ACE in the endothelium (r = .85, P < .001) or adventitia (r = .78, P < .001), and mean arterial pressure correlated significantly with free ACE in the endothelium (r = .52, P < .05) or adventitia (r = .53, P < .05) and with the plasma Ang II-to-Ang I ratio (r = .53, P < .05). Light microscopic autoradiographs of 125I-351A binding revealed a marked inhibition of ACE by perindopril in both layers of the vascular wall. CONCLUSIONS: The present demonstrates that long-term administration of perindopril potently inhibits both endothelial and adventitial ACE to a comparable degree in the human internal mammary artery. These results indicate that perindopril effectively penetrates the vascular wall to inhibit ACE in the adventitia, thus providing evidence that perindopril may be beneficial in inhibiting both circulating Ang II and its local formation in the vascular wall.

Aged↗
PubMed2004

Vascular adventitia generates neuronal progenitors in the monkey hippocampus after ischemia.

In the adult hippocampus, neurogenesis proceeds in the subgranular zone (SGZ) of the dentate gyrus (DG), but not in the cornu Ammonis (CA). Recently, we demonstrated in monkeys that transient brain ischemia induces an increase of the neuronal progenitor cells in the SGZ, but not in CA1, in the second week after the insult. To identify the origin of primary neuronal progenitors in vivo, we compared the postischemic monkey DG and CA1, using light and electron microscopy, focusing on specific phenotype markers, as well as the expression of neurotrophic factors. Laser confocal microscopy showed that 1-3% of 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the SGZ after 2-96 h labeling were also positive for neuronal markers such as TUC4, betaIII tubulin, and NeuN on days 9 and 15. In contrast, despite the presence of numerous BrdU-positive cells, CA1 showed no neurogenesis at any time points, and all the progenitors were positive for glial markers: Iba1 or S-100beta on days 4, 9, and 15. Highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive cells were abundant in the SGZ, but were absent in CA1. On day 9, most of the immature neurons positive for betaIII-tubulin in SGZ showed an increase in PSA-NCAM immunoreactivity. The immunoreactivity of brain-derived neurotrophic factor (BDNF) was abundant at the vascular adventitia of the SGZ, but was absent at the adventitia of CA1. BrdU-positive progenitor cells were frequently seen in the vicinity of proliferating blood vessels. Ultrastructural analysis indicated that most of the neuronal progenitor cells and microglia originated from the pericytes of capillaries and/or adventitial cells of arterioles (called vascular adventitia). The detaching adventitial cells showed mitotic figures in the perivascular space, and the resultant neuronal progenitor cells made contact with dendritic spines associated with synaptic vesicles or boutons. These data implicate the vascular adventitia as a novel potential source of neuronal progenitor cells in the postischemic primate SGZ.

Animals↗
PubMed1992

Catecholamine histofluorescence depletion in the infarcted brain parenchyma but not in the adventitia of the occluded cerebral arteries in rats.

The effect of acute cerebral ischemia on the catecholamine-containing nerve fibers in the brain parenchyma and in the adventitia of the cerebral arteries was studied in the rat. Unilateral cerebral ischemia was produced with an intraluminal thread technique which does not damage the adventitia of cerebral arteries. One to three days after surgery the ischemic damage of the brain was consistently observed in the territory of the middle cerebral artery of the operated side. Depletion of catecholamine histofluorescence was observed in the infarcted brain parenchyma. However, in the adventitia of the middle cerebral arteries of the operated side, catecholamine histofluorescence remained intact. No detectable changes in fluorescence were observed in the brain parenchyma or adventitia of the cerebral arteries in the contralateral side. The results indicate that the perivascular catecholamine-containing nerve fibers are not impaired by the intraluminal occlusion of the cerebral artery in the early stage of ischemia.

Animals↗
PubMedDate not supplied

B-Lymphocytes in plaque and adventitia of coronary arteries in two patients with rheumatoid arthritis and coronary atherosclerosis: preliminary observations.

OBJECTIVES: To describe the subtypes of lymphocytes in coronary arteries of two patients with rheumatoid arthritis (RA) and coronary artery disease (CAD). MATERIALS AND METHODS: The Mayo Clinic database was searched for patients with RA and CAD who underwent an autopsy in 2001. Medical records were reviewed, and coronary arteries were examined microscopically. The percentage of B- and T-lymphocytes was determined using histomorphometry on representative sections stained with CD20 and CD3 antibodies, respectively. RESULTS: Two men were diagnosed with RA at ages 52 and 70 years and died at ages 60 and 82 years. One sustained an acute myocardial infarction 2 years prior to the diagnosis of RA and had stable CAD until an arrhythmic death. The other developed congestive heart failure secondary to ischemic heart disease 5 years after RA was diagnosed. Both patients had severe three-vessel CAD with both stable fibrocalcific plaques and acute lesions. B- and T-lymphocytes were identified in the plaque and adventitia of all coronary arteries. The mean percentage of B-lymphocytes was 37% to 52% in the plaque and 78% to 85% in the adventitia, while that of T-lymphocytes was 38% to 51% and 28%, for plaque and adventitia, respectively. CONCLUSIONS: In typical CAD, lymphocytic infiltrates are almost exclusively T-cells. In contrast, the two patients with RA and CAD showed prominent infiltrates of B-lymphocytes within plaques and adventitia. Thus, the leukocytic response in atherosclerotic plaques may be altered in patients with autoimmune disorders. This warrants further study.

Aged↗
PubMed2004

Effects of adrenomedullin on cell proliferation in rat adventitia induced by lysophosphatidic acid.

Lysophosphatidic acid (LPA) is a bioactive phospholipid having growth factor-like activity on fibroblasts and is involved in cardiovascular diseases such as hypertension and heart failure by inducing vascular remodeling, characterized by fibroblast proliferation and migration in adventitia. Among various bioactive factors that LPA works with, adrenomedullin (ADM) is a multiple functional peptide with an important cytoprotective effect against cardiovascular damage. We studied rat aortic adventitia to explore the possible paracrine/autocrine interaction between endogenous ADM and LPA. LPA stimulation of the adventitia to secrete ADM and express its mRNA was concentration dependent. ADM inhibited LPA-induced proliferation in adventitial cells and attenuated the activity of mitogen-activated protein kinase (MAPK) stimulated by LPA. In contrast, treatment with specific antagonists of the ADM receptor potentiated the LPA-induced proliferation in adventitial cells. We concluded that LPA stimulates the adventitia to produce and secrete ADM, which in turn regulates the vascular biological effects of LPA.

Adrenomedullin↗
PubMed1996

Smooth muscle cell migration into intima and adventitia during development of transplant vasculopathy.

Smooth muscle cell (SMC) migration from the medial layer into the intima is a characteristic feature of transplant vasculopathy and is thought to be regulated by locally produced cytokines. We studied the expression of smooth muscle alpha-actin, PDGF B-ligand and, PDGF alpha- and beta-receptors in rat aortic allografts with transplant vasculopathy using immunohistochemistry. At two weeks, an intense expression of PDGF B-ligand and, PDGF alpha- and beta-receptors was found in the neointima and adventitia. Medial SMC expression decreased with time in parallel with accumulation of smooth muscle alpha-actin in the neointima and adventitia. PDGF expression persisted in the adventitia. Prolonged ischemic storage time resulted in an increase in the number of alpha-actin-positive SMCs in the intima of syngeneic grafts. These data indicate that SMCs migrate into both the intima and adventitia. This migration may be induced, at least in part, by PDGF produced by graft invading monocyte-derived macrophages.

Actins↗
PubMed2003

Shear modulus of porcine coronary artery: contributions of media and adventitia.

The epicardial coronary arteries experience significant torsion in the axial direction due to changes in the shape of the heart during the cardiac cycle. The objective of this study was to determine the torsional mechanical properties of the coronary arteries under various circumferential and longitudinal loadings. The coronary artery was treated as a two-layer composite vessel consisting of intima-medial and adventitial layers, and the shear modulus of each layer was determined. Eight porcine hearts were obtained at a local abattoir, and their right coronary and left anterior descending arteries were isolated and tested in vitro with a triaxial torsion machine (inflation, longitudinal stretch, and circumferential twist). After the intact vessel was tested, the adventitia was dissected away, leaving an intact media that was then tested under identical triaxial loading conditions. We proposed a biomechanical analysis to compute the shear modulus of the adventitia from the measured shear moduli of the intact vessel and the media. To validate our predictions, we used four additional hearts in which the shear modulus of the adventitia was measured after dissection of media. Our results show that the shear modulus does not depend on the shear stress or strain but varies linearly with circumferential and longitudinal stresses and in a nonlinear way with the corresponding strains. Furthermore, we found that the shear modulus of the adventitia is larger than that of the intact vessel, which is larger than the vessel media. These results may have important implications for baroreceptor sensitivity, circulation of the vasa vasorum, and coronary dissection.

Animals↗
PubMed2001

[The collagen of the restenosis post angioplasty with stent: Is its origin in intima or adventitia?].

BACKGROUND: Restenosis post stenting is due to the deposit of extracellular matrix, mainly collagen in the neointima. Controversy exists regarding if collagen is generated locally or by immigration from the adventitia. AIM: To study the fibrocellular response after stent implantation in rabbit iliac arteries. To observe, by immunohistochemistry and in situ hybridization, if collagen type I mRNA is expressed in the neointima, in the media or in the adventitia. MATERIAL AND METHODS: Thirty eight white rabbits (New Zealand) of 4 kg received an hypercholesterolemic diet during 1 month. After this period, in all but 6 of them, an angioplasty with stent implantation was performed via right carotid artery in both iliac arteries, using a 1:1.3 relationship regarding the reference vessel. Angiograms were performed at day 0, 4, 21, and 40, followed by paraffin fixation of the injured segments, immunohistochemistry for alpha-actin and in situ hybridization to detect procollagen type I (alpha 1R1) mRNA. RESULTS: No hybridization was observed in non injured arteries or at day 0 (n = 6). Expression of alpha 1R1 mRNA was observed in the neointima starting at day 4 after stenting (n = 8). At day 21 (n = 8) hybridization of procollagen type I was not only observed in the neointima, but also in the media, which became equally intense in both areas. At day 40 (n = 6) hybridization was observed similarly in the media and adventitia. CONCLUSIONS: In this model, hybridization of procollagen type I started in the neointima, then involved the media and finally the adventitia. This finding might be useful for designing therapies to be delivered locally at the end of an angioplasty to prevent collagen deposition in the neointima.

Angioplasty, Balloon↗
PubMed1992

Presence of angiotensin converting enzyme in the adventitia of large blood vessels.

BACKGROUND: Angiotensin converting enzyme (ACE) is present in the endothelial cells of all vascular beds. There are, however, many reports of converting enzyme activity in blood vessels not associated with the endothelium. METHODS: ACE was localized in large blood vessels of a number of mammals by in vitro autoradiography using the radioligand 125I-351A. To characterize this binding further, immunohistochemistry was performed on rabbit aorta using polyclonal antisera raised to two different preparations of rabbit lung ACE. RESULTS: In all of the blood vessels studied, which included the rabbit pulmonary artery, rabbit, dog and sheep aorta, human internal mammary artery and human saphenous vein, high levels of radioligand binding were found in endothelial cells, as expected. In addition, a very high density of punctate binding was observed interspersed between diffuse moderate labelling in the adventitia. Immunoreactivity was confined to the endothelium of both the intima and the vasa vasorum of the adventitia. The immunostaining correlated well with the autoradiography. The ACE inhibitors lisinopril and perindoprilat displayed similar high affinities in competing for the binding of 125I-351A to the endothelium and adventitia of the sheep aorta, suggesting that at these two sites the radioligand was binding to ACE. CONCLUSIONS: We find that ACE in the adventitia of large blood vessels is confined to the vaso vasorum. The results of this study help to explain the findings of many studies that ACE activity persists in endothelium-denuded blood vessels and also reveals a source of ACE distant from the luminal endothelial surface.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1980

[Cystic degeneration of the adventitia of the popliteal artery (author's transl)].

Cystic degeneration of the adventitia of the popliteal artery is a rare clinico-angiographic diagnosis in the chronic ischaemia syndrome of the lower extremity. If the three cardinal signs occur concomitantly, namely, intermittent ischaemia syndrome, unilocular manifestation near the joint and clearly limited filling defect in the arteriogram, diagnosis can be made with a high measure of certainty. Among our angiographically examined patients, we observed, in the course of one year, three male patients who presented the full picture of the disease with regard to clinic, localisation and angiographic findings. Intraoperatively it was not possible to establish a connection between adventitia cyst and neighbouring articular capsule; this applies, in fact, to all our cases. Histologically we found in one case, in the hollow spaces of the adventitia, an indication of the possible existence of a synovial recess, so that the scattering of mucine-secreting endothelium of the joint into the vascular adventitia is again brought up for discussion.

Aged↗
PubMed1977

The effect of monoamine oxidase and catechol O-methyltransferase inhibitors on the accumulation and metabolism of [l-3H] norepinephrine by the adventitia and media of rabbit aorta.

The effects of catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) inhibitors on the accumulation and metabolism of [l-3H] norepinephrine ([l-3H]NE) were studied in the isolated adventitia and media of rabbit aorta. The COMT inhibitors produced a greater inhibition of O-methylation in the isolated media than in the isolated adventitia. In addition, exposure to these drugs was associated with an increased level of [l-3H]NE and increased formation of the catechol deaminated metabolites by the isolated media but not by the isolated adventitia. The effects of these drugs on the balance of the oxidized vs. reduced forms of the deaminated metabolites was interpreted to mean that 3-methoxy-4-hydroxyphenylethylglycol is formed from normetanephrine rather than from 3,4-dihydroxyphenylethylglycol whereas 3-methoxy-4-hydroxymandelic acid is formed from 3,4-dihydroxymandelic acid. 3,4-Dihydroxyphenylethylglycol does not seem to serve as a substrate for 3-methoxy-4-hydroxyphenylethylglycol becuase it rapidly passes out of the tissue after it is formed. Parglyline and iproniazid markedly decreased deamination of [l-3H]NE and increased the tissue level of [l-3H]NE. However, these drugs produced little if any compensatory increase in O-methylation of [l-3H]NE. The effects of these drugs are compatible with the hypothesis that adrenergic nerves contain MAO and vascular smooth muscle contains MAO and COMT. Harmaline seemed to block both MAO and COMT. Based on the effects of clorgyline and deprenyl and the other MAO inhibitors tested, the isolated adventitia seems to contain primarily type A MAO and the isolated media seems to contain primarily type B MAO.

Animals↗
PubMed2001

Adenoviral mediated uteroglobin gene transfer to the adventitia reduces arterial intimal hyperplasia.

PURPOSE: The aim of this study was to investigate the feasibility of gene transfer of uteroglobin, a potent anti-inflammatory and immunomodulatory agent, via adenoviral mediated gene transfer to the adventitia in the mouse carotid ligation injury model and also to investigate the efficacy of uteroglobin in reducing neointimal hyperplasia. METHODS: Forty-five C57bl/6NHSD mice were anesthetized and left common carotid artery ligation was performed. Adenoviral vector encoding the uteroglobin gene (Ad.UG; 15 microl of 1.35 x 10(11) pfu/mL) was applied to the adventitia of the injured artery in 16 mice. In our control groups, 16 mice received adenoviral vector encoding the beta-galactosidase reporter gene (Ad.lacZ; 15 microl of 1.0 x 10(11) pfu/mL) and 13 mice received PBS only. Six mice from each group were sacrificed at 4 days for carotid artery protein extraction and Western blot analysis. The remainder were harvested at 30 days for histologic and morphometric analysis. The intima/media area ratios were calculated for each artery. The results were analyzed and compared using ANOVA and Bonferroni/Dunn post hoc testing. RESULTS: Two mice from the LacZ group and one from the PBS group died before the 30-day endpoint. Uteroglobin expression was demonstrated in the Ad.UG treated arteries by Western blot analysis. Morphometric analysis demonstrated a statistically significant reduction in the intima/media area ratio of Ad.UG treated carotids compared to controls. There was a reduction of intima/media ratio with Ad. UG treatment of 68% compared to Ad.lacZ treatment (P < 0.0001) and 62% compared to PBS treatment (P = 0.0006). There was no statistical difference between the control groups. CONCLUSION: Adenoviral mediated gene transfer via the adventitia is an effective mode of gene delivery. Adventitial uteroglobin gene transfer using an adenoviral vector induces uteroglobin protein production and significantly reduces neointimal hyperplasia in the mouse carotid ligation injury model.

Adenoviridae↗
PubMed1980

Effects of in vitro and in vivo exposure to insulin upon glucose carbon accumulation in rat aorta: different patterns of response for intima-media and adventitia.

We have studied the effect of insulin upon the accumulation of glucose carbon into the intima-media and the adventitia of rat aorta following in vitro exposure by adding insulin to the incubation medium, and in vivo exposure by producing relative hyperinsulinemia during life and subsequently incubating excised tissue in a medium containing no insulin. Hyperinsulinemia in vivo was either (1) endogenous--following 1.5-2 hr of refeeding after a 48-hr fast--or (2) exogenous--following an i.v. injection of insulin. For adventitia, a significant stimulation was found after both in vitro (+ 53%, p < 0.001) and in vivo exposure to insulin (+ 96%, p < 0.01 with endogenous insulin; + 75%, p < 0.05 with a dosage of 2 U/kg of exogenous insulin). For intima-media, the stimulation was weak and insignificant after in vitro exposure (+ 11%, p > 0.30), but became important and significant after in vivo exposure to insulin (+ 100%, p < 0.001 with endogenous insulin; + 50%, p < 0.05 with a dosage of 0.5 U/kg and + 49%, p < 0.05 with a dosage of 2 U/kg of exogenous insulin). For the in vivo exposure experiments, we found a significant linear correlation (r = 0.611, p < 0.005) between plasma insulin concentrations and glucose carbon accumulations into intima-medias of control and refed rats. These results establish the insulin sensitivity of the adventitia and show a sensitivity of intima-media only to in vivo insulin exposure. These different behaviors of intima-media in vivo and in vitro may have a hemodynamic basis.

Animals↗
PubMed2006

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice.

Angiotensin II (A-II), the major effector peptide of the renin angiotensin system potently accelerates progression of atherosclerosis. To investigate its effects on vascular inflammatory mechanisms, we elucidated vascular cytokine expression during early lesion development in A-II-infused atherosclerosis-prone LDLR-/- mice. Male LDLR-/- mice were placed on a "Western" high-fat diet for 4 weeks, followed by sham or A-II infusion for 7 weeks. Equal blood pressures and elevations in serum lipids were seen in both groups. Mice were sacrificed when significant A-II-induced plaque development was first detectable, aortae were explanted and culture media assayed for secreted cytokines. Nine cytokines were significantly induced with interleukin-6 (IL-6) being the most highly secreted. Local IL-6 production was confirmed by in situ mRNA hybridization and immunostaining, where the most abundant IL-6 was found in the aortic adventitia, with lesser production by the medial and intimal layers. Immunofluorescence colocalization showed IL-6 expression by fibroblasts and activated macrophages. Activation of downstream IL-6 signaling mediated by the Jak-STAT3 pathway was demonstrated by inducible phospho-Tyr705-STAT3 formation in the adventitia and endothelium (of IL-6+/+ mice only). These findings define cytokine profiles in the A-II infusion model and demonstrate that IL-6, produced by activated macrophages and fibroblasts in the adventitia, induces the Jak-STAT3 pathway during early A-II-induced atherosclerosis.

Angiotensin II↗
PubMed2005

Modulatory role of the adventitia on noradrenaline and angiotensin II responses role of endothelium and AT2 receptors.

OBJECTIVE: We have studied the modulatory role of the adventitia on vascular tone and nitric oxide (NO) availability in response to noradrenaline (NA) and angiotensin II (Ang II). METHODS: Changes in isometric tension were determined in carotid arteries from 3-month-old Sprague-Dawley rats denuded from adventitia (-A) and compared to intact rings (+A). NO availability was assessed by the fluorescent NO indicator, 4,5-diaminofluorescein diacetate (DAF-2). RESULTS: Responses to NA (10(-10) to 10(-6) M) were: (i) significantly lower in -A compared to +A rings; (ii) equally enhanced in +A and -A rings without endothelium; and (iii) reduced in +A and -A rings incubated with superoxide dismutase (SOD; 15 U/ml). Responses to Ang II (10(-10) to 10(-7) M) were: (i) similar between +A and -A segments; (ii) equally reduced in both groups by SOD; and (iii) increased by endothelial denudation in both +A and -A arteries. Blockade of AT2 receptors with PD 123,319 (10(-7) M) significantly increased Ang II-induced contractions in +A rings. In segments preincubated with losartan (10(-5) M) and precontracted with NA (10(-7) M), Ang II elicited a relaxation that was abolished by l-NAME (10(-4) M), PD 123,319 (10(-7) M), and endothelium or adventitial removal. NO availability was increased in carotid rings stimulated with Ang II, but not with NA. This NO release was blocked by PD 123,319 (10(-7) M) and endothelium denudation. CONCLUSIONS: These results suggest that the adventitia differently modulates responses to vasoconstrictors and that it is a key layer in Ang II-induced contractions, mediating NO release from the endothelium via AT2 receptors. This increase in NO counterbalances basal superoxide release.

Angiotensin II↗