Adventitial Mast Cells Research Articles

Allergic Eosinophilic Vasospastic Angina – A New Endotype

Histamine has been implicated in the pathogenesis of vasospastic angina, with coronary artery adventitial mast cells being a potential histamine source. Since histamine is a key mediator of allergic responses, the concept of allergic vasospastic angina (Kounis syndrome) has been introduced; however, histamine release may occur via both allergic and non-allergic pathways. Eosinophil-mediated allergic responses may induce vasospastic angina via histamine release.

TanshinoneⅡA attenuates carotid artery atherosclerosis by deactivating mast cells in adventitia

Objective: To investigate the effects of tanshinone ⅡA on atherosclerosis plaque formation and adventitial mast cells activation in high-fat-diet induced Apo E(-/-) mice model. Methods: Sixteen 8-week-old Apo E(-/-)male mice and eight 8-week-old C57BL/6 male mice were randomly allocated into following group: the control group (C57BL/6 + carboxymethyl cellulose per gavage), the atherogenic group (Apo E(-/-)+carboxymethyl cellulose per gavage) and the tanshinoneⅡA intervention group (Apo E(-/-)+30 mg/kg tanshinone ⅡA per gavage). All three groups were fed with high-fat-diet for 26 weeks. Tanshinone ⅡA/carboxymethyl cellulose was applied by the method of gavage administration 6 weeks before execution. After 26 weeks, tumor necrosis factor-α (TNF-α) andinterleukin (IL)-6 levels in serum were assessed by ELISA. Carotid artery was removed, fixed with paraformaldehyde, embedded with paraffin and sectioned. Percentage of stenosis was evaluated on HE stained sections. Plaque progression was assessed by Movat staining. Toluidine blue staining was used to evaluate mast cells infiltration and activation. Immunochemistry staining was used to assess 5-HT, TNF-α and IL-6 expression. mRNA expression of mast cell marker Fcer1a in adventitial tissue was detected by real time-PCR. Results: After high-fat-diet for 26 weeks, the mice in the atherogenic group showed advanced atherosclerosis, tanshinoneⅡA intervention reduced the percentage of carotid artery stenosis caused by atherosclerotic plaque formation ((58.48±8.07)% vs. (80.31±4.08)%, P<0.05). Compared with the atherogenic group, tanshinone ⅡA intervention group had lower level of TNF-α ((12.39±1.62)pg/ml vs. (17.44±1.42)pg/ml) and IL-6 ((116.24±12.16)pg/ml vs. (166.05±19.09)pg/ml) in serum, lower TNF-α ((20 145±1 556) vs. (25 288±1 671)) and IL-6 ((25 688±1 604) vs. (35 286±4 198)) expression in adventitia (all P<0.05). TanshinoneⅡA intervention also decreased the number of mast cells infiltration and activation, reduced 5-HT expression and mast cell marker Fcer1a mRNA relative expression in adventitia (all P<0.05). Conclusions: Tanshinone ⅡA could attenuate induced by high-fat-diet carotid artery atherosclerosis in Apo E(-/-) mice. The protective effect of tanshinoneⅡA is probably mediated through reducing the number and activation percentage of mast cells, decreasing the release of inflammatory cytokines and inflammation of carotid artery in adventitia.

Accumulation of eosinophils, mast cells, and basophils in the spleen and the coronary arteries in anaphylactic deaths: is the Kounis hypersensitivity associated syndrome present?

In a very interesting study published in Forensic Science,Medicine, and Pathology [1] it was found that measure-ment of eosinophils and mast cells in the spleen combinedwith serum tryptase measurement could diagnose anaphy-laxis and anaphylactic death with a high degree of cer-tainty. The authors stated that anaphylactic death cannot bediagnosed by autopsy alone or by counting mast cells in thelung and airways because these methods have failed to giveconsistent results. The search for other tissues infiltrated byallergic inflammatory cells could prove of paramountimportance in diagnosing anaphylactic sudden death. Theyrecommended that splenic tissue should be sampled forimmunohistochemical examination in all cases of unwit-nessed sudden death.Eosinophils, mast cells, and basophils are importanteffector cells in the allergic response and they have beenimplicated in the pathogenesis of anaphylaxis. Whilediagnosing the cause of sudden death is a challenging taskfor both physicians and forensic pathologists, anaphylacticetiology is rarely suspected. Frequently, sudden death casesare attributed to myocardial involvement, but unrecognizedanaphylaxis may accompany up to 13 % of sudden unex-pected deaths in adults [2]. There is experimental andclinical evidence that anaphylaxis is frequently associatedwith myocardial involvement due to coronary artery spasmand thrombosis manifesting as Kounis type I and Kounistype II variant [3]. Some experiments have shown thatanaphylactic cardiac damage is not due to peripheralvasodilation but is the result of the action of anaphylacticmediators on the coronary vasculature [4]. Clinically, thereare patients with anaphylactic cardiac shock who do notrespond to fluid replacement but need anti-allergic andcurrent myocardial infarction protocol treatment, thusdenoting that the heart and especially the coronary arteriesare primarily affected [5, 6]. However, differentiatingglobal myocardial hypoperfusion from a primary cardiacmyocardial suppression due to mast cell mediator action isclearly challenging and combined myocardial suppressionand peripheral vasodilatation might occur simultaneously.There are reports of sudden death due to coronary arteryspasm in which the coronary arteries are involved. In apatient with repeated episodes of coronary spasm, who diedsuddenly following cessation of his treatment, the numberof adventitial mast cells was found to be increased [7]. Inthis patient, histologic sections in all three major coronaryarteries, including the area of spasm, were stained withtoluidine blue and showed increased mast cells. In the samereport, two additional subjects with sudden cardiac deathalso had increased mast cells in their coronary arteries withthe highest counts in atherosclerotic and hemorrhagic pla-ques. Furthermore, coronary arteries of cardiac patients arehyper-reactive and contain stores of amines deriving frominflammatory cells that are the main culprits in inducingcoronary spasm [8]. Type I and type II variants of theKounis syndrome have led to coronary artery spasm andsudden death in two patients with drug-eluting stents. It is

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation

Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPA-mediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell deficient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability.

Do Adventitial Mast Cells Contribute to the Pathogenesis of Ascending Thoracic Aorta Aneurysm?

The precise pathogenesis of the ascending aortic aneurysm (AscAA) remains to be determined. Mast cells in the adventitia of human AscAA lesions may play a role in this pathogenesis. Adventitial mast cell density per 10 high-power fields (0.25 mm(2)) was assessed in multiple biopsy samples, from aneurysmal aortic sections (n = 41) and control (nondilated) aortic specimens (n = 50), stained by orcein-Giemsa method, an inexpensive (<$1) method. In a multivariable adjusted logistic regression model, using AscAA as the dependent variable, mast cell density was found to be an independent predictor of AscAA occurrence (odds ratio = 2.21; 95% confidence interval = 1.58-3.08; P < .001). Receiver operating characteristic curve analysis showed that the proposed cutoff value of ≥ 3 mast cells per 10 high-power fields was very sensitive to detect AscAA occurrence, yielding a sensitivity of 90% with a specificity of 80%. In conclusion, a significant increase in the number of mast cells in the adventitia of human ascending aortic lesions proposes a role for these cells in the pathogenesis of AscAA.

Substance P mediated adventitial mast cell activation induces intraplaque hemorrhage in advanced atherosclerosis

Previously, we demonstrated that mast cells play an important role in plaque destabilization. However, the endogenous trigger for (peri)vascular mast cell activation during atherosclerosis is unresolved. Here, we show that perivascular mast cell content correlates with the number of perivascular neurofilament positive nerve fibers in human coronary atherosclerotic plaques (P<0.05, r=0.42). Our attention turned to the neuropeptide substance P (SP) as mediator of mast cell activation. Local perivascular administration of SP to advanced carotid artery plaques in apoE−/− mice did not affect plaque size at 3 days after challenge; however the number of adventitial mast cells was significantly enhanced in SP-treated mice compared to controls (4.9±0.8 versus 2.2±0.5 mast cells/square mm adventitial tissue, P<0.01).

Cold exposure and adipose nitric oxide and mast cells: influence on aorta contractility

Both nitric oxide (NO) and mast cells play important roles in adipose and vascular tissue biology. Chronic cold stress decreases the sensitivity of vascular smooth muscle to various contractile agents including norepinephrine (NE). In our previous cold exposure study we found that the contractile response of isolated rat aortas to NE was significantly reduced, and the number of rat aortic adventitial mast cells decreased. Histologically and functionally, white and brown adipose tissue (WAT and BAT) can be distinguished. Beyond its significance in energy store/release and heat production, adipose tissue secretes multiple signaling molecules that have endocrine and paracrine role in the regulation of vascular functions. The aims of the present study were to examine chronic cold exposure-induced alterations in (i) the concentration of NO released from selected regions of WAT and BAT in female and male rats, (ii) the histochemistry of white and brown adipose mast cells, and (iii) whether adipose-derived NO affects the contraction of isolated rat aorta to NE. Twelve females and 12 males Spraque-Dawley rats (150-200 g body weight) were used. The rats were exposed to a cold/freely moving stress for 2 hours each day for 5 consecutive days. At the end of cold exposure, the rats were sacrificed, and samples of thoracic aorta with associated periadventitial adipose tissue (tunica adiposa) were obtained. WAT and BAT were isolated from subcutaneous abdominal and interscapular areas, respectively. The concentration of NO was measured by capillary electrophoresis and mast cells were evaluated histochemically. The response of aorta smooth muscles to NE was recorded in the isolated organ bath. To determine whether adipose-derived NO affects aorta contraction to NE, cumulative dose response curves to NE (10 -8 -10 -3 M) were obtained with or without isolated WAT/BAT suspended in the organ bath medium. In control animals, a gender-related significant difference in NO production in both WAT and BAT was found, NO levels being significantly higher in female than male rats. Data from the contractile response of isolated aorta to NE suggest that receptor affinity to NE is significantly different between female and male controls. Presence of BAT and WAT (isolated from cold-exposure animals) in the bath changed the response of aorta smooth muscle to NE. Displaying a gender dimorphism, BAT/WAT-derived NO, or other vasorelaxing factors, seem to reduce receptor density and/or affinity to NE. Adipose mast cell histochemistry also showed diversity in respect to subtype, gender, and cold exposure. Altogether, we found (i) a gender difference in adipose-released NO and in adipose mast cell histochemistry to cold exposure, and (ii) peripheral adipose tissues affect aortic contractile responses to NE likely by a NO-mediated pathway during cold exposure, suggesting that adipose tissue may limit cold-induced excessive vasoconstriction. Our ongoing study aims at the evaluation of whether aortic tunica adiposa itself could also contribute to this phenomenon. Adipobiology 2009; 1: 67-75.

Short Communication: The Neuropeptide Substance P Mediates Adventitial Mast Cell Activation and Induces Intraplaque Hemorrhage in Advanced Atherosclerosis

Although we and others have recently shown that mast cells play an important role in plaque progression and destabilization, the nature of the actual trigger for (peri)vascular mast cell activation during atherosclerosis is still unresolved. In this study, we confirm that perivascular mast cell content correlates with the number of nerve fibers in the adventitia of human coronary atherosclerotic plaque specimen. Because peripheral C-type nerve fibers secrete, among others, substance P, a potent mast cell activator, we set out to study effects of adventitial administration of this neuropeptide on mast cell dependent destabilization of carotid artery plaques in apolipoprotein E-deficient (apoE(-/-)) mice. Substance P treatment significantly enhanced the number and activation status of adventitial mast cells compared to controls and promoted intraplaque hemorrhages. These phenomena could be prevented by coadministration of the neurokinin-1 receptor antagonist spantide I and did not occur in mast cell deficient apoE(-/-) mice, establishing the critical involvement of mast cells in substance P-elicited plaque destabilization. Our data suggest that neurotransmitters such as substance P are capable of promoting mast cell dependent plaque destabilization and provide a new, direct link between neural factors and vascular inflammation.

Abstract 5066: Substance P Mediated Adventitial Mast Cell Activation Induces Intraplaque Hemorrhage in Advanced Atherosclerosis

Previously, we and others have shown that mast cells, present in intima and adventitia of advanced atherosclerotic lesions, play an important role in plaque progression and destabilization. However, the nature of the endogenous trigger for activation of these (peri)vascular cells during atherosclerosis is still unresolved. In this study, we show that perivascular mast cell content as demonstrated by CD117 staining correlates with the number of neurofilament + nerve fibers in the adventitia of human coronary atherosclerotic plaque specimens (P&lt;0.05, r=0.42), suggestive of neural regulation of mast cell activation. Our attention turned to the neuropeptide substance P (SP) as mediator of mast cell activation via the neurokinin-1 receptor. Local perivascular administration of SP (0.1 nmol in 25% (w/v) F-127 pluronic gel) to advanced carotid artery plaques in apoE −/− mice did not affect plaque size at 3 days after challenge (SP: 67±14*10 3 μ m 2 versus controls: 51±10*10 3 μ m 2 , P=NS), however the number of adventitial mast cells was significantly enhanced in SP treated mice compared to PBS controls (4.9±0.8 versus 2.2±0.5 mast cells/mm 2 adventitial tissue, P&lt;0.01). Also, mast cell activation status was increased in the SP challenged group (56±9% compared to 29±9% in controls, P&lt;0.05). This was accompanied by a significant increase in the incidence of intraplaque hemorrhages (IPHs) in SP treated mice (5/12 compared to 0/15 in controls, P=0.01). SP mediated mast cell recruitment was inhibited by co-administration of the neurokinin-1 receptor antagonist Spantide-I (2.6±0.4 mast cells/mm 2 adventitial tissue, P&lt;0.01), while in these mice hardly any IPHs occurred (1/16, P=0.06). Furthermore, SP was not effective in inducing IPHs in advanced carotid artery plaques of mast cell deficient apoE −/− Kit(W −sh /W −sh ) mice (1/18, P&lt;0.05), establishing the critical involvement of mast cells in SP elicited plaque destabilization. In conclusion, our data suggest that neurotransmitters such as SP are capable of promoting mast cell dependent plaque destabilization and our study thus provides a new, direct link between neural factors and vascular inflammation involving mast cells, which may be particularly relevant in acute cardiovascular syndromes.

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (+/+) rats following periaortic application of calcium chloride (CaCl2) treatment but not in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E-deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA.

Vanilloid receptor TRPV1, sensory C-fibers, and activation of adventitial mast cells: A novel mechanism involved in adventitial inflammation

The immunological mechanisms on adventitial inflammation has received much attention, while the contribution of nerves to adventitial inflammation has largely been ignored. Although the mechanism of initial chemotaxis of the adventitial inflammatory cells remains unknown, vascular nerves were frequently found in the inflammatory lesions of coronary adventitia and adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries. The sensory nerves in contact with adventitial mast cells contained the neuropeptides SP and CGRP. These neuropeptides play an important role in the amplification of tissue injury by the increase of both vascular permeability and neutrophil recruitment, and the term ''neurogenic inflammation'' has been coined. Activation of adventitial mast cells, with ensuing release of vasoactive compounds, may cause vasoconstriction in atherosclerotic coronary segments. Therefore, we hypothesize that adventitial vanilloid receptor TRPV1 and sensory C-fibers may play a pistol role for adventitial inflammation.

Abstract 1193: Mast Cell Activation Promotes Leukocyte Recruitment And Adhesion To The Atherosclerotic Plaque

Activated mast cells have been identified in the perivascular tissue of human coronary artery plaques. As mast cells have been described to release a whole array of chemokines including interleukin 8 (IL-8) and MIP1 α, we propose that activated mast cells play a pivotal role in leukocyte recruitment at advanced stages of atherosclerotic plaque development. Peritoneal mast cells of either C57Bl/6 or mast cell deficient Kit(W −sh /W −sh ) mice were activated by injection of compound 48/80 (1.2 mg/kg). Interestingly, mast cell activation led to a massive neutrophil influx into the peritoneal cavity at 3 hours after activation (controls: 1 ± 0.7*10 4 Gr1 + -neutrophils/ml up to 8 ± 0.2*10 4 Gr1 + neutrophils/ml at 3 hours after activation, *P&lt;0.05), while neutrophil numbers in Kit(W −sh /W −sh ) mice were not affected by compound 48/80 administration. Moreover, increased levels of CXCR2 + Gr1 + neutrophils (t=0: 0.55 ± 0.07% versus t=3 hours: 1.00 ± 0.12%, *P&lt;0.05) were observed after mast cell activation. Next, we investigated whether mast cell activation also translated in induced leukocyte adhesion to advanced atherosclerotic plaques. Adventitial mast cells of advanced collar aided carotid artery plaques were activated by local application of a dinitrophenyl-BSA (DNP) challenge in ApoE −/− mice. Three days later, the carotid artery segments carrying the plaques were isolated and perfused ex vivo with rhodamine labeled leukocytes, showing a dramatically increased number of adherent leukocytes after mast cell activation (49 ± 6 versus 19 ± 4 leukocytes/microscopic field for DNP versus control plaques, respectively, **P&lt;0.001). Strikingly, antibody blockade of either the CXCR2 or VCAM-1 receptor VLA-4 on labeled leukocytes completely inhibited leukocyte adhesion to the atherosclerotic plaque (*P&lt;0.05), while blockade of CCR1, -3 and -5 with Met-RANTES had no effect. In conclusion, our data suggest that chemokines such as IL-8 released from activated perivascular mast cells induce leukocyte recruitment and adhesion to the atherosclerotic plaque, aggravating the ongoing inflammatory response and thus effecting plaque destabilization. We propose that mast cell stabilization could be a new therapeutic approach in the prevention of acute coronary syndromes.

Th-W61:6 Number of aortic adventitial mast cells and severity of aortic valve thickening are increased in uremic apoE knockout mice

Th-W61:6 Number of aortic adventitial mast cells and severity of aortic valve thickening are increased in uremic apoE knockout mice

Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator.

Intraplaque neovascularization and hemorrhage may facilitate plaque progression. We studied expression of basic fibroblast growth factor (bFGF), a potent angiogenic mediator, by mast cells (MCs) in human coronary plaques with increasing degrees of atherosclerosis. Normal and atherosclerotic coronary segments were collected from 30 autopsied subjects. Immunohistochemical methods were used to detect MCs, bFGF, and microvessels. Both adventitial and intimal MCs showed intracytoplasmic granular staining for bFGF, and bFGF-positive extracellular granules were observed close to the MCs. Increased numbers of bFGF-positive MCs were detected in neovascularized areas of plaques, and there was a positive correlation between numbers of bFGF-positive MCs and microvessels in both the intima and adventitia. In plaques, the highly neovascularized areas contained increased numbers of bFGF-positive MCs compared with the adjacent nonvascularized areas, where only few MCs were present. Importantly, the proportion of intimal MCs expressing bFGF increased with increasing severity of atherosclerosis. The present work reveals a novel source of bFGF in human coronary arteries, the intimal and adventitial MCs. The association of bFGF-positive MCs with microvessels and with the severity of atherosclerosis suggests that coronary MCs, by releasing bFGF, may play a role in angiogenesis and progression of coronary plaques.

Adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries.

The number of activated mast cells is increased in the adventitia of coronary segments with plaque rupture and in spastic atherosclerotic coronary segments. Neurogenic activation of mast cells has been demonstrated previously in other tissues. Here we identified and quantified contacts between mast cells and nerves in the adventitia of normal and atherosclerotic coronary segments. Normal (types 0 or I) and atherosclerotic (lesion types II, III, and IV) coronary segments from 22 unselected autopsy cases were stained for mast cells and sensory nerves by a histochemical double-labeling method. Contacts between mast cells and sensory nerves were quantified morphometrically and also identified by confocal microscopy. Coronary arteries obtained during heart transplantation were stained for the neuropeptides capable of stimulating mast cells, ie, substance P and calcitonin gene-related peptide. In the adventitia of atherosclerotic coronary segments with type IV lesions, the numbers of mast cells and mast cell-nerve contacts (104+/-15 mast cells/mm(2) and 30+/-5 nerve contacts/mm(2); mean+/-SEM) were significantly greater than in segments with type III lesions (79+/-12 [P<0.001] and 24+/-6 [P<0.001]), those with type II lesions (54+/-4 [P<0.001] and 12+/-2 [P<0.001]), or those with normal intima (31+/-3 [P<0.001] and 4+/-1 [P<0.001]). The nerve fibers connected with mast cells contained both substance P and calcitonin gene-related peptide, which identified them as sensory nerves. Neurogenic stimulation of mast cells in the adventitia of coronary arteries may release vasoactive compounds, such as histamine and leukotrienes, which can contribute to the complex neurohormonal response that leads to abnormal coronary vasoconstriction.

Endothelin receptor antagonism ameliorates mast cell infiltration, vascular hypertrophy, and epidermal growth factor expression in experimental diabetes.

Vascular hypertrophy, a feature of experimental and human diabetes, has been implicated in the pathogenesis of the microvascular and macrovascular complications of the disease. In the present study, we sought to examine the role of endogenous endothelin and its relation to vascular growth factors in the mediation of vascular hypertrophy in experimental diabetes and to examine the contribution of mast cells to this process. Vessel morphology, endothelin, growth factor gene expression, and matrix deposition were studied in the mesenteric arteries of control and streptozotocin-induced diabetic Sprague-Dawley rats treated with or without the dual endothelin(A/B) receptor antagonist bosentan (100 mg x kg(-1) x d(-1)) during a 3-week period. Compared with control animals, diabetic animals had significant increases in vessel weight, wall-to-lumen ratio, mast cell infiltration, extracellular matrix deposition, and gene expression of epidermal growth factor (EGF) and transforming growth factor-beta(1). In diabetic, but not control, vessels, not only were EGF mRNA and endothelin present in endothelial cells, but also their expression was observed in adventitial mast cells. Immunoreactive endothelin was present in the media of mesenteric vessels of diabetic, but not control, animals. Bosentan treatment significantly reduced mesenteric weight, wall-to-lumen ratio, mast cell infiltration, matrix deposition, and EGF mRNA but did not prevent the overexpression of transforming growth factor-beta(1) mRNA in diabetic rats. These findings suggest that endogenous endothelin and EGF may play a role in diabetes-induced vascular hypertrophy and that mast cells may be pathogenetically involved in this process.

The Effect of Stress and in Vivo Vasoactive Intestinal Peptide (VIP) Treatment on the Response of Isolated Rat Aorta to Norepinephrine, Angiotensin II and Vasopressin, and Adventitial Mast Cells

The effects of cold-restraint stress, repeated over 3 days, and treatment of rats with vasoactive intestinal peptide (VIP) on the contractile responses of isolated aorta to vasoconstrictors, and on aortic adventitial mast cells were investigated. Stress significantly reduced the contractile response of rat aorta smooth muscle to norepinephrine (NE), angiotensin II (Ang II) and vasopressin (VP). Decreased sensitivity to NE, Ang II and VP may result from decreased receptor density, and affinity or reduced effector efficacy. Stress induced degranulation, decreased the number and changed the granular content of mast cells; all degranulated mast cells were stained with alcian blue, and the percentage of safranin staining cells was decreased. Given prior to stress, VIP reversed the reduced contractile responses and sensitivity of aorta to NE and Ang II but had no effect on VP subsensitivity. VIP also inhibited stress-induced degranulation of mast cells, and after VIP only alcian blue-stained mast cells were seen. When VIP was given to non-stressed rats, the contractile response of the aorta to NE, but not Ang II or VP, was increased compared with control. Mast cell count was decreased in the adventitia of non-stressed VIP treated rats. The results indicate that stress decreases the heparin content of mast cells and VIP has an additive effect. In conclusion, VIP modulates both stress-induced mast cell activity and reduced sensitivity of aorta smooth muscle to NE and Ang II. It can be suggested that VIP may moderate some effects of stress on vascular pathophysiology.

Association Between Myocardial Infarction and the Mast Cells in the Adventitia of the Infarct-Related Coronary Artery

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. 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. 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.

Increase in atherosclerosis and adventitial mast cells in cocaine abusers: An alternative mechanism of cocaine-associated coronary vasospasm and thrombosis

Coronary vasospasm has been implicated as a cause of myocardial ischemia and sudden cardiac death in cocaine abusers. However, the mechanism or mechanisms remain unknown. Autopsy records (n = 5,871) from the medical examiner's files at Baltimore, Maryland and northern Virginia were examined and 495 persons (8.4%) were identified with positive toxicologic findings for cocaine. Of these, six subjects (1.2%) had total thrombotic occlusion, involving primarily the left anterior descending coronary artery. The mean number of adventitial mast cells per coronary segment and the degree of atherosclerosis were determined. These observations were compared with findings in age- and gender-matched subjects who died from cocaine overdose and in patients who had sudden cardiac death (acute thrombosis) without a history of illicit drug abuse.There were significantly more mast cells in subjects with cocaine-associated thrombosis than in the other groups. The number of mast cells showed a significant correlation with the degree of cross-sectional luminal narrowing (r = 0.68) in subjects with cocaine-associated thrombosis but not in subjects with sudden death due to thrombosis (r = 0.34, p < 0.03). Subjects with cocaine-associated thrombosis also had significant coronary atherosclerosis without plaque hemorrhage (five had one or more vessels with >75% cross-sectional area luminal narrowing) despite a mean age of 29 ± 2 years.These findings suggest that adventitial mast cells may potentiate atherosclerosis and vasospasm, thrombosis and premature sudden death in long-term cocaine abusers.

Cluster Headache: Ultrastructural Evidence for Mast Cell Degranulation and Interaction with Nerve Fibres in the Human Temporal Artery

It has been suggested that histamine plays an important role in the pathogenesis of cluster headache. In addition, both neurogenic and vascular components have been described during cluster headache attacks without an obvious anatomical link between them. Our ultrastructural observations of human temporal arteries from cluster headache patients and their comparison to those from a control group strongly suggest that mast cells may be this link. Mast cells in both groups show a very close apposition with nerve fibres, suggesting a functional interaction between them. Moreover, in the cluster headache group exclusively, adventitial mast cells show profound morphological modifications suggesting progressive degranulation. These data strongly suggest that mast cells could be directly or indirectly involved in the pathophysiology of cluster headaches.