Periadventitial Fat Research Articles

Effects of the thromboxane receptor antagonist S18886 in the porcine coronary circulation

Thromboxane A2 (TxA 2 ) is a potent coronary vasoconstrictor that has been implicated in promoting decreases in myocardial perfusion in a variety of (patho)-physiologic conditions. S18886 is a promising orally-active TxA 2 receptor antagonist currently approved for investigational clinical use. However, the coronary vascular effects of S18886 are unknown and its specificity and affinity for the thromboxane receptor in the coronary circulation remain unclear. We tested the hypothesis that administration of S18886 dose-dependently attenuates coronary vasoconstriction to the TxA 2 mimetic U46619 without influencing coronary responses to prostaglandin F 2α , acetylcholine, or smooth muscle depolarization (K + ). Experiments to test this hypothesis were performed in male (n = 5) and female (n = 6) domestic swine. Hearts were excised and the left circumflex coronary artery isolated, cleaned of periadventitial fat, and cut into 3 mm rings. Isometric tension of coronary artery rings was measured in response to log order increments of U46619 (1 nM to 1 μM) with and without S18886 (0.1-100 nM). Similar isometric studies were conducted with prostaglandin F 2α (10 nM-10 μM), acetylcholine (0.1-10 μM), and KCl (5-90 mM). U46619 induced concentration dependent increases in tension development of isolated coronary artery rings (average EC50 of 42 ± 19 nM). Incubation of coronary arteries with S18886 (1 nM) significantly attenuated coronary vasoconstriction to U46619 resulting in a rightward shift of the EC50 to 187 ± 38 nM (P < 0.02). Vehicle had no effect on U46619-induced contractions. Higher concentrations of S18886 (10nM and 100nM) dose-dependently reduced U46619-induced contractions by 77% ± 3 and 93% ± 6 respectively. S18886 (1 nM) antagonized coronary vasoconstriction of prostaglandin F2α (10 μM) by 68% ± 5 (P < 0.0001) but had no effect on either acetylcholine or KCl-induced contraction. Data from this investigation indicate that S18886 is an effective antagonist of U46619-induced vasoconstriction in the porcine coronary circulation. While S18886 does not influence coronary smooth muscle response to either acetylcholine or activation of L-type Ca 2+ channels, attenuation of prostaglandin F 2α suggests the antagonists specificity may extend beyond TxA 2 receptor signaling. NIH R01HL158723 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Immunophenotypic analysis of the chronological events of tissue repair in aortic medial dissections.

Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections. Subsequent immunohistochemically staining was performed with the following markers: (myeloperoxidase (neutrophils), citrullinated-Histone 3 (neutrophil extracellular traps), CD68 (macrophages), CD3 (T-cells), CD31 and CD34 (endothelial cells), and smooth muscle actin. Immune stained sections were scored semi-quantitatively. Histologically, five cases were identified as stage I, 16 as II, 7 as III and 4 as IV. Additional immunostaining for smooth muscle cells and endothelial cells altered the classification in 25% of cases (all in groups II and III). Immunostaining and semi-quantitative grading of involvement of neutrophils, macrophages and NETs also provided specific distribution patterns over the 4 age categories, including unexpected involvement of the peri adventitial fat tissue. In conclusion, it appears that semi-quantitative immunohistochemistry of resident vascular wall cells, inflammatory cells and NETS represents a useful adjunct in detailed histopathological grading of the chronological age of aortic dissections.

Specific imaging of atherosclerotic plaque lipids with two-wavelength intravascular photoacoustics.

The lipid content in plaques is an important marker for identifying atherosclerotic lesions and disease states. Intravascular photoacoustic (IVPA) imaging can be used to visualize lipids in the artery. In this study, we further investigated lipid detection in the 1.7-µm spectral range. By exploiting the relative difference between the IVPA signal strengths at 1718 and 1734 nm, we could successfully detect and differentiate between the plaque lipids and peri-adventitial fat in human coronary arteries ex vivo. Our study demonstrates that IVPA imaging can positively identify atherosclerotic plaques using only two wavelengths, which could enable rapid data acquisition in vivo.

Chemerin and CMKLR1 expression in human arteries and periadventitial fat: a possible role for local chemerin in atherosclerosis?

BackgroundDepending on their anatomical location, different fat depots have a different capacity to produce bioactive peptides, called adipokines. Adipokines produced by periadventitial fat have been implicated in the pathogenesis of vascular disease, including atherosclerosis. Chemerin is an adipokine with an established role in immunity, adipose tissue function and metabolism, acting in autocrine, paracrine and endocrine manners. We investigated the protein expression of chemerin and its receptor, CMKLR1, in human aortas, coronary vessels and the respective periadventitial adipose tissue and correlated their expression with the presence of atherosclerosis.MethodsImmunohistochemistry for chemerin and CMKLR1 was performed on human aortic and coronary artery samples including the periadventitial adipose tissue. Aortic and coronary atherosclerotic lesions were assessed using the AHA classification.ResultsChemerin immunopositivity was noticed in both periadventitial fat depots, in vascular smooth muscle cells and foam cells in atherosclerotic lesions. Periadventitial fat and foam cell chemerin immunopositivity was statistically significantly correlated with the severity of atherosclerosis in both locations. CMKLR1 was expressed in vascular smooth muscle cells and foam cells in aortic and coronary vessels with atherosclerotic lesions. CMKLR1 immunostaining in foam cells was statistically significantly correlated with aortic atherosclerosis.ConclusionsOur results lend some support to a presumable role of locally produced chemerin in the progression of atherosclerotic lesions, possibly acting through its CMKLR1 receptor. Further research will elucidate the role of chemerin signaling in atherosclerosis.

Adiponectin/T-cadherin and apelin/APJ expression in human arteries and periadventitial fat: implication of local adipokine signaling in atherosclerosis?

Adipose tissue is considered an endocrine organ, producing bioactive peptides, called adipokines. Adipokines produced by periadventitial fat have been implicated in the pathogenesis of vascular disease, including atherosclerosis. Adiponectin has established antiatherogenic actions, while the role of T-cadherin as an adiponectin receptor is not fully elucidated. The apelinergic system, consisting of apelin and its APJ receptor, is a mediator of various cardiovascular functions and may also be involved in the atherosclerotic process. We investigated the protein expression of adiponectin, T-cadherin, apelin and APJ in human aortas, coronary vessels, and the respective periadventitial adipose tissue and correlated their expression with the presence of atherosclerosis and clinical parameters. Immunohistochemistry for adiponectin, T-cadherin, apelin, and APJ was performed on human aortic and coronary artery samples including the periadventitial adipose tissue. Aortic and coronary atherosclerotic lesions were assessed using the american heart association (AHA) classification. Adiponectin immunostaining, of varied intensity, was detected only in adipocytes, while T-cadherin was localized to vascular smooth muscle cells (VSMCs) and endothelial cells. Apelin immunostaining was detected in adipocytes, VSMCs, endothelial cells, and foam cells in atherosclerotic lesions, while APJ was found in VSMCs and endothelia. Periadventitial adiponectin and VSMC T-cadherin expression were negatively correlated with atherosclerosis in both sites, as was VSMC apelin expression. Several other - depot specific - associations were observed. Our results suggest a possible role for T-cadherin as a mediator of antiatherogenic adiponectin actions, while they support the putative antiatherogenic profile for apelin and its APJ receptor in human arteries. Further research is absolutely necessary to confirm these notions. Periadventitial adipose tissue adipokines are implicated in vascular physiology and pathology. Adiponectin/T-cadherin and apelin/APJ immunoreactivity is detected in human aortas and coronary arteries. Adiponectin/T-cadherin and apelin/APJ expression patterns were found to be inversely associated with human aortic and coronary atherosclerosis.

Abstract 467: Nitric Oxide-Mediated Regulation of the Adiponectin-Adiponectin Receptor Pathway Following Arterial Injury

Objectives Nitric oxide (NO) has been shown to limit the development of neointimal hyperplasia; however, little is known about its effects on the adventitia. Adiponectin is a molecule that originates from periadventitial adipose tissue and has been shown to negatively regulate neointimal growth. Thus, we hypothesize that removal of periadventitial fat from the arterial wall will negatively impact the ability of NO to inhibit the development of neointimal hyperplasia following injury. Methods The carotid artery injury model was performed on 11-week-old Sprague Dawley rats. Animal models underwent either removal of all periadventitial fat from the artery at the time of surgery (absent) or no disturbance of the periadventitial fat (present). Treatment groups included control, injury, and injury + NO (PROLI/NO, 10mg). Arteries were harvested at 2 weeks. Morphometric analysis was performed using ImageJ software. Immunofluorescent staining was performed for the adiponectin receptor (AR) and assessed using blinded grading (scale 0-4). Results Morphometric analysis revealed a 29% increase in neointima development in the absent vs. present group (p<0.001). With the application of NO, there was a greater decrease in intima area in the absent than the present group (93% vs. 77%, p<0.001). The results were similar for media area (50% vs. 37%, p<0.001) and the intima/media area ratio (86% vs. 65%, p<0.001). While AR staining showed no significant difference in the media or adventitia with the application of NO in the present group, AR staining was significantly increased in both the media (57%, p=0.009) and adventitia (37%, p<0.05) with the application of NO in the absent group. Conclusions Removal of the source of periadventitial adiponectin resulted in more neointimal hyperplasia following arterial injury, but a paradoxical NO-mediated increase in AR levels and corresponding responsiveness to NO therapy. These data suggest that AR expression is upregulated in the absence of adiponectin by NO. Further studies that identify the mechanism by which NO may regulate adiponectin may provide a novel therapeutic target to prevent neointimal hyperplasia.

Vasodilating effect of capsaicin on rat mesenteric artery and its mechanism

To investigate the vasodilating effect of capsaicin (CAP) on rat mesenteric artery and its mechanism. The third branch of the superior mesenteric artery in male Sprague-Dawley rat (250-350 g) was excised, the periadventitial fat and connective tissue were removed and the mesenteric artery was dissected into 2 mm rings. Each ring was placed in a 5 ml organ bath of DMT 610M system and the tension was recorded. CAP (10(-9)-10(-5) mol/L) relaxed endothelium-intact and endothelium-denuded mesenteric artery pre-constricted by phenylephrine (10(-5) mol/L), and the vasodilation in endothelium-intact mesenteric artery was stronger than that in endothelium-denuded one. Pretreatment with either L-NAME (3 X10(-4) mol/L), an inhibitor of nitric oxide synthase(NOS), or CGRP8-37 (2 X 10(-6) mol/L), an antagonist of calcitonin gene-related peptide (CGRP), for 30 min significantly attenuated the relaxation of endothelium-intact mesenteric artery induced by CAP. CGRP (10(-10)-3 X10(-8) mol/L) relaxed endothelium-intact and endothelium-denuded mesenteric artery pre-constricted by phenylephrine, and the vasodilation in endothelium-intact mesenteric artery was stronger than that in endothelium-denuded one. Substance P did not relax the mesenteric artery pre-constricted by phenylephrine. CAP has partial endothelium-dependent relaxation effect on rat mesenteric artery, which may be mediated by activating the endothelial NOS-NO pathway. The endothelium-independent relaxation in rat mesenteric artery induced by CAP may be mediated by CGRP.

Abstract 659: Chemerin Connects Fat to Blood Pressure

Obesity and hypertension have become comorbid in near epidemic proportion, yet their biological connection is still largely a mystery. We hypothesized that the peptide chemerin (TIG2) is a candidate for connecting fat deposits (both perivascular and visceral) to elevated blood pressure. The normal Sprague Dawley or deoxycorticosterone acetate salt (DOCA) rat was used as the model. Real time RT-PCR demonstrated that chemerin was synthesized in periadventitial fat (PVAT) around the aorta. Immunohistochemical experiments showed that the primary receptor for chemerin, ChemR23, was expressed in the tunica media and endothelial layer and not in resident inflammatory cells of the artery. The potent analog chemerin-9 (1 nM — 3 uM) caused a concentration-dependent isometric contraction in isolated aorta and superior mesenteric artery that was modest in tissues at baseline [∼6-11% phenylephrine (PE) maximum contraction] but significantly amplified in the presence of the nitric oxide synthase inhibitor nitro-L-arginine (LNNA; 2.5 fold increase in maximum), endothelial removal (5.95 fold increase) or agonist-induced tone (3.2 fold increase). Chemerin-induced contraction in tissues incubated with LNNA was concentration-dependently antagonized by the novel ChemR23 antagonist CCX832, demonstrating a new role for ChemR23. Arteries from the DOCA-salt hypertensive rat demonstrated endothelial dysfunction, and chemerin-induced maximum contraction from baseline was markedly increased in the aorta (DOCA = 16+3.6%, Sham = 6.7 + 2.2% PE contraction) and superior mesenteric artery (DOCA=57.9+12.8, Sham = 11.2+2.9 % PE contraction; p<0.05). These data support a new role for chemerin as a vasoactive substance and a potential connector of the biological activity of the adipose tissue and liver (sources of chemerin) to blood pressure regulation, especially in conditions of endothelial dysfunction.

Indoleamine 2,3-diooxygenase in periaortic fat: mechanisms of inhibition of contraction

Indoleamine 2,3-dioxygenase (IDO) metabolizes L-tryptophan to L-kynurenine, promotes immunosuppression, and has been described as a consumer of superoxide. We discovered IDO expression in periaortic fat and tested the hypothesis that periarterial IDO functionally reduces agonist-induced contraction. Our model was the thoracic aorta, abdominal aorta, and superior mesenteric artery of the male Sprague-Dawley rat. Periaortic fat from the thoracic aorta stained intensely for IDO, the brown fat marker uncoupling protein-1, and oil red O as a general lipid marker. White fat around the mesenteric artery and abdominal aorta stained less for IDO; brown fat was less abundant. IDO activity (kynurenine-to-tryptophan ratio via HPLC) was detected in visceral and mesenteric artery fat (ratio: ∼4) but was highest in perithoracic aortic fat (ratio: 10 ± 1.1). In isometric contractile experiments, periadventitial fat reduced ANG II-induced thoracic aortic (with fat: 34% of without fat) and mesenteric artery (with fat: 63% of without fat) maximal contraction. In contrast, periadventitial fat did not reduce agonist-induced contraction in the abdominal aorta. The IDO inhibitor 1-L-methyltryptophan (1-MT) reversed the fat-induced reduction of ANG II-induced contraction in the thoracic aorta but not in the mesenteric artery. The IDO metabolite kynurenine relaxed the thoracic aorta only at high (9 mM) concentrations, whereas the downstream metabolite quinolinic acid (1 mM) relaxed the contracted thoracic aorta (∼80%). 1-MT did not correct the reduction in basal superoxide levels observed in the presence of perithoracic aortic fat. We conclude that IDO is an enzyme active primarily in brown fat surrounding the thoracic aorta and depresses aortic contractility.

Oxidative stress and inflammation in the endothelial dysfunction of obesity: a role for nuclear factor kappa B?

Oxidative stress and inflammation in the endothelial dysfunction of obesity: a role for nuclear factor kappa B?

Endovascular Injury Induces Rapid Phenotypic Changes in Perivascular Adipose Tissue

Accumulating evidence suggests that adipose tissue not only stores energy but also secretes various bioactive substances called adipocytokines. Periadventitial fat is distributed ubiquitously around arteries throughout the body. It was reported that inflammatory changes in the periadventitial fat may have a direct role in the pathogenesis of vascular diseases accelerated by obesity. We investigated the effect of endovascular injury on the phenotype of perivascular fat. Endovascular injury significantly upregulated proinflammatory adipocytokines and downregulated adiponectin within periadventitial fat tissue in models of mouse femoral artery wire injury and rat iliac artery balloon injury. Genetic disruption of tumor necrosis factor (TNF)-alpha attenuated upregulation of proinflammatory adipocytokine expression, with reduced neointimal hyperplasia after vascular injury. Local delivery of TNF-alpha to the periadventitial area enhanced inflammatory adipocytokine expression, which was associated with augmented neointimal hyperplasia in TNF-alpha-deficient mice. Conditioned medium from a coculture of 3T3-L1 and RAW264 cells stimulated vascular smooth muscle cell proliferation. An anti-TNF-alpha neutralizing antibody in the coculture abrogated the stimulating effect of the conditioned medium. Our findings indicate that endovascular injury induces rapid and marked changes in perivascular adipose tissue, mainly mediated by TNF-alpha. It is suggested that the phenotypic changes in perivascular adipose tissue may have a role in the pathogenesis of neointimal hyperplasia after angioplasty.

Periadventitial Adipose Tissue Plays a Critical Role in Vascular Remodeling

Obesity is associated with a high incidence of cardiovascular complications. However, the molecular link between obesity and vascular disease is not fully understood. Most previous studies have focused on the association between cardiovascular disease and accumulation of visceral fat. Periadventitial fat is distributed ubiquitously around arteries throughout the body. Here, we investigated the impact of obesity on inflammation in the periadventitial adipose tissue and on lesion formation after vascular injury. High-fat, high-sucrose feeding induced inflammatory changes and decreased adiponectin expression in the periadventitial adipose tissue, which was associated with enhanced neointima formation after endovascular injury. Removal of periadventitial fat markedly enhanced neointima formation after injury, which was attenuated by transplantation of subcutaneous adipose tissue from mice fed on regular chow. Adiponectin-deficient mice showed markedly enhanced lesion formation, which was reversed by local delivery, but not systemic administration, of recombinant adiponectin to the periadventitial area. The conditioned medium from subcutaneous fat attenuated increased cell number of smooth muscle cells in response to platelet derived growth factor-BB. Our findings suggest that periadventitial fat may protect against neointimal formation after angioplasty under physiological conditions and that inflammatory changes in the periadventitial fat may have a direct role in the pathogenesis of vascular disease accelerated by obesity.

Beyond the Adventitia

See related article, pages 541–549 The anatomy of the arterial wall has traditionally been divided into 3 distinct regions, forming concentric layers surrounding the blood vessel lumen. The intima, consisting of a single layer of endothelial cells in direct contact with the lumen; the media, containing layers of smooth muscle cells and extracellular elastin fibers; and the adventitia, composed largely of collagen and other extracellular matrix protein but also containing fibroblasts, inflammatory cells, and a separate microvasculature. The earliest studies on the role of inflammation in the pathogenesis of atherosclerosis focused on the role of endothelial and smooth muscle cells in disease progression; ie, the cell types that reside within the inner arterial layers.1 Some of the earliest observations demonstrated that that an upregulation of adhesion molecules on the endothelial surface initiates the disease process, resulting in the recruitment of monocytes into the vessel wall. More advanced lesions are characterized by the migration and proliferation of the smooth muscle cells, which further contribute to the remodeling of the arterial microstructure. The accumulation of cells and matrix proteins within the developing plaque leads to a lumen narrowing and an altered intimal microenvironment. The adventitia, on the other hand, has historically been regarded as a minor participant in the disease process, and its functional role in plaque formation and development have largely been overlooked. However, the inflammatory response that occurs in the setting of atherosclerosis clearly involves adventitia. Contributions of adventitia-derived inflammatory cells, cytokines, and microvasculature likely contribute significantly in many different vascular disease states.2,3 The involvement of the adventitia in vascular pathology suggest that there is an “outside-in” component to atherosclerosis that is synergistic with the traditional “inside-out” view of atherogenesis. However, arteries are obviously contained within surrounding tissue which, in the case of most vascular beds, is …

A Reduction in the Amount and Anti-Contractile Effect of Periadventitial Mesenteric Adipose Tissue Precedes Hypertension Development in Spontaneously Hypertensive Rats

The aim of this study was to determine whether alterations in periadventitial adipose tissue and its anti-contractile effect precede hypertension development. We used 4-week-old male Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), which were pre-hypertensive. Vascular function was studied in the perfused mesenteric bed (MB, 1.5 mL/min). MB weight was lower in SHR (8.0 +/- 0.3 mg/g body weight) than in WKY (9.0 +/- 0.3 mg/g body weight) rats. Concentration-response curves to KCI (6 to 75 mmol/L) and to acetylcholine (10(-9) to 10(-5) mol/L) were similar between groups. Contractile responses to serotonin (10(-9) to 10(-5) mol/L) were significantly higher in SHR compared to WKY. 4-Aminopyridine (4-AP, 2 mmol/L), a blocker of Kv channels, induced a similar increase in perfusion pressure in both strains. However, 4-AP (2 mmol/L) significantly increased the contractile response to serotonin (10(-9) to 10(-5) mol/L) only in WKY. The anti-contractile effect of fat was confirmed by a comparison of (+) fat and (-) fat mesenteric arteries, which revealed that 4-AP significantly enhanced contractions only in (+) fat rings from WKY. These results show that alterations in visceral periadventitial fat mass and function in SHR precede hypertension, suggesting a constitutive mechanism independent of age and the hypertensive state.

Abstract 1041: Endovascular Injury Affects Adipocytokine Profile Of The Periadventitial Adipose Tissue

Background: Adipose tissue secretes not only proinflammatory cytokines but also anti-inflammatory cytokines such as adiponectin. Arteries are surrounded by abundant periadventitial fat tissues, which have been suggested to play a role in maintenance of vascular homeostasis. Here, we investigated whether endovascular injury affects the profile of adipocytokines expressed by perivascular adipose tissue (PAT). Methods and Results: First, the femoral artery of C57BL/6 mice was overstretched by insertion of a large wire. Real-time PCR analysis revealed that wire injury markedly down-regulated adiponectin expression (0.64±0.09 fold, p<0.01) and up-regulated expression of proinflammatory cytokines, TNF alpha, IL-6, PAI-1, and MCP-1 (p<0.01) 1 day after overstretch within PAT. Neutrophils and macrophages accumulated in the adventitia surrounding the injury site at 1 day after the injury. Inflammation was associated temporally with the expression of mRNAs encoding inflammatory adipocytokines. Second, the iliac artery of Wistar rats was dilated percutaneously with a balloon for 1 minute. There were up-regulation of proinflammatory cytokines and down-regulation of adiponectin 1 and 3days after endovascular injury within PAT (p<0.05). Third, abdominal aortas removed from Wistar rat with PAT were dilated with a balloon PTCA catheter for 1 minute ex vivo. After stretching, aortas with PAT were cultured for 6 hours, and we observed increased synthesis of proinflammatory cytokines and decreased synthesis of adiponectin within PAT (p<0.05). Fourth, the stimulation of TNF alpha, which markedly increased in injured arteries, caused significant down-regulation of adiponectin expression and up-regulation of IL-6, PAI-1, and MCP-1 in 3T3L1-derived adipocytes (p<0.01). Conclusions: Angioplasty may induce the changes of perivascular cytokines expression. The accumulation of neutrophils and macrophages at PAT in injured arteries and/or increased proinflammatory expression of injured vascular arteries may reflect these proinflammatory activities of PAT. Increased proinflammatory cytokines and decreased anti-inflammatory cytokine adiponectin in PAT possibly may have a role in vascular remodeling following PTCA-mediated vascular injury.

Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction

Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1−/− mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)–salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in several cells, including some immune cells. Accordingly, adoptive transfer of T cells lacking the angiotensin type I receptor or a functional NADPH oxidase resulted in blunted angiotensin II–dependent hypertension and decreased aortic superoxide production. Angiotensin II increased T cell markers of activation and tissue homing in wild-type, but not NADPH oxidase–deficient, mice. Angiotensin II markedly increased T cells in the perivascular adipose tissue (periadventitial fat) and, to a lesser extent the adventitia. These cells expressed high levels of CC chemokine receptor 5 and were commonly double negative (CD3+CD4−CD8−). This infiltration was associated with an increase in intercellular adhesion molecule-1 and RANTES in the aorta. Hypertension also increased T lymphocyte production of tumor necrosis factor (TNF) α, and treatment with the TNFα antagonist etanercept prevented the hypertension and increase in vascular superoxide caused by angiotensin II. These studies identify a previously undefined role for T cells in the genesis of hypertension and support a role of inflammation in the basis of this prevalent disease. T cells might represent a novel therapeutic target for the treatment of high blood pressure.

Dysfunction of AQP7 in the periadventitial fat: A novel trigger of atherosclerosis

Vascular adventitial lesion as a new etiological factor of atherosclerosis (AS) has been confirmed by the results of several different animal models, and some evidence supports adventitial inflammation as the main cause, but the exact mechanism is still elusive. The data from some studies confirm that some link exists between the adventitial inflammation (which also might happen in the periadventitial fat) and atherosclerotic lesions. Aquaporin7 (AQP7) as an aquaglyceroporin, which regulates the permeation of glycerol through the cell membrane and located in the adipose tissue, shows some relationship with obesity. The result of the studies about AQP7-knockout mice and different expression of AQP7 in the cutaneous abdominal adipose tissue among people with different body types proved this phenomenon. Meanwhile, some degree of dysfunction of AQP7 has been proved in the obese. Until now, no study has shown us the data on the correlation of the expression of AQP7 in the periadventitial fat with the severity of atherosclerotic lesions. It is proposed that dysfunction of AQP7 in the periadventitial fat may trigger the adventitial inflammation. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of AS and the development of a novel agent for this disorder.

The Role of Periadventitial Fat in Atherosclerosis

It has become increasingly evident that adipose tissue is a multifunctional organ that produces and secretes multiple paracrine and endocrine factors. Research into obesity, insulin resistance, and diabetes has identified a proinflammatory state associated with obesity. Substantial differences between subcutaneous and omental fat have been noted, including the fact that omental fat produces relatively more inflammatory cytokines. Periadventitial fat, as a specific adipose tissue subset, has been overlooked in the field of atherosclerosis despite its potential diagnostic and therapeutic implications. To review (1) evidence for the role of adventitial and periadventitial fat in vessel remodeling after injury, (2) the relationship between adventitial inflammation and atherosclerosis, (3) the association between periadventitial fat and plaque inflammation, and (4) the diagnostic and therapeutic implications of these roles and relationships for the progression of atherosclerosis. We present new data showing greater uptake of iron, administered in the form of superparamagnetic iron oxide, in the periadventitial fat of atherosclerotic mice than in control mice. In addition, macrophage density in the periadventitial fat of lipid-rich plaques is increased compared with fibrocalcific plaques. There is a striking paucity of data on the relationship between the periadventitial fat of coronary arteries and atherosclerosis. Greater insight into this relationship might be instrumental in making strides into the pathophysiology, diagnosis, and treatment of coronary artery disease.

The Role of Periadventitial Fat in Atherosclerosis

Abstract Context.—It has become increasingly evident that adipose tissue is a multifunctional organ that produces and secretes multiple paracrine and endocrine factors. Research into obesity, insulin resistance, and diabetes has identified a proinflammatory state associated with obesity. Substantial differences between subcutaneous and omental fat have been noted, including the fact that omental fat produces relatively more inflammatory cytokines. Periadventitial fat, as a specific adipose tissue subset, has been overlooked in the field of atherosclerosis despite its potential diagnostic and therapeutic implications. Objective.—To review (1) evidence for the role of adventitial and periadventitial fat in vessel remodeling after injury, (2) the relationship between adventitial inflammation and atherosclerosis, (3) the association between periadventitial fat and plaque inflammation, and (4) the diagnostic and therapeutic implications of these roles and relationships for the progression of atherosclerosis. D...

Protein Kinase A-dependent Translocation of Hsp90α Impairs Endothelial Nitric-oxide Synthase Activity in High Glucose and Diabetes

Diabetes mellitus (DM) and high glucose (HG) are known to reduce the bioavailability of nitric oxide (NO) by modulating endothelial nitric-oxide synthase (eNOS) activity. eNOS is regulated by several mechanisms including its interaction with heat shock protein (Hsp) 90. We previously discovered that DM in vivo and HG in vitro induced the translocation of Hsp90alpha to the outside of aortic endothelial cells. In this report we tested the hypothesis that translocation of Hsp90alpha is responsible for the decline in NO production observed in HG-treated cells. We found that HG increased phosphorylation of Hsp90alpha in a cAMP-dependent protein kinase A-dependent manner, and that this event was required for translocation of Hsp90alpha in porcine aortic endothelial cells. Furthermore, preventing translocation of Hsp90alpha protected from the HG-induced decline in eNOS.Hsp90alpha complex and NO production. Notably, DM increased phosphorylation of Hsp90alpha and reduced its association with eNOS in the aortic endothelium of diabetic rats. These studies suggest that translocation of Hsp90alpha is a novel mechanism by which HG and DM impair eNOS activity and thereby reduce NO production.