MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis.

RATIONALE: Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. OBJECTIVE: The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent. METHODS AND RESULTS: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P<0.001), reduced intramural neoangiogenesis ( P<0.001), and prevented intimal layer hyperplasia ( P<0.001). rMMP-9 amplified all domains of vasculitic activity, promoted assembly of T-cell infiltrates ( P<0.05), intensified formation of new microvessels ( P<0.001), and worsened intimal thickening ( P<0.001). Systemic delivery of N-acetyl-proline-glycine-proline-a matrikine produced by MMP-9-mediated gelatinolysis-had limited vasculitogenic effects. CONCLUSIONS: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.

Rediscovering the wound hematoma as a site of hemostasis during major arterial hemorrhage.

BACKGROUND: Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical hemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial hemostasis, or how these commonly used treatments might influence hemostasis. OBJECTIVES: (i) To use a swine model of femoral artery bleeding to understand the perivascular hemostatic response to contained arterial hemorrhage. (ii) To directly confirm the association between hemodynamics and bleeding velocity. (iii) To observe the feasibility of delivering an activated clotting factor directly to internal sites of bleeding using a simplified angiographic approach. METHODS: Ultrasound was used to measure bleeding velocity and in vivo clot formation by elastography in a swine model of contained femoral artery bleeding with fluid resuscitation. A swine model of internal pelvic and axillary artery hemorrhage was also used to demonstrate the feasibility of local delivery of an activated clotting factor. RESULTS: In this model, clots formed slowly within the peri-wound hematoma, but eventually contained the bleeding. Central hemodynamics correlated positively with bleeding velocity. Infusion of recombinant human activated factor VII into the injured artery near the site of major internal hemorrhage in the pelvis and axillae was feasible. CONCLUSIONS: We rediscovered that clot formation within the peri-wound hematoma is an integral component of hemostasis and a feasible target for the treatment of major internal bleeding using activated clotting factors delivered using a simplified angiographic approach.

Impact of cranial and axillary/subclavian artery involvement by color duplex sonography on response to treatment in giant cell arteritis.

OBJECTIVE: Color duplex sonography (CDS) today is broadly used in the diagnostic workup of patients with suspected cranial or extracranial giant cell arteritis (GCA). This study aimed to determine the prognostic impact of the disease pattern assessed by CDS on the treatment response in GCA. METHODS: This was a retrospective, longitudinal follow-up study of 43 patients who were diagnosed with GCA at our institution between 2002 and 2010. All patients underwent CDS of the temporal and subclavian/axillary arteries at baseline and were observed for at least 6 months. Vasculitis was sonographically characterized by a circumferential, hypoechogenic wall thickening. According to the CDS findings, patients were categorized into patients with involvement of the subclavian/axillary arteries only (group A1, n = 17), patients with involvement of both the subclavian/axillary arteries and the temporal arteries (group A2, n = 9), and patients with isolated cranial GCA (group B, n = 17). Data on recurrences, corticosteroid doses, and steroid-sparing agents were extracted from the medical records. Treatment response over time was analyzed by Kaplan-Meier curves with log-rank testing. RESULTS: The mean follow-up time was 25.4 months and did not differ between groups (P = .4). Patients in group A1 were significantly younger than patients in groups A2 and B (P < .01). The interval between symptom onset and diagnosis was significantly longer in groups A1 and A2 compared with group B (P < .01). The number of recurrences per month was significantly higher in group A2 compared with group A1 and group B (A1, 0.07; A2, 0.13; B, 0.03; P < .01). Whereas there were no significant differences in the mean time until a daily prednisolone dose <10 mg was reached, patients in group A2 more frequently required steroid-sparing agents (A1, 24%; A2, 56%; B, 24%; P = .04). CONCLUSIONS: Extensive vascular involvement of both the temporal and subclavian/axillary arteries, as depicted by CDS, may be associated with a poor treatment response in GCA.

Effects of Carnoy's solution on blood vessels of the axillary fossa of rats.

Carnoy's solution is applied to reduce the recurrence of odontogenic keratocysts and unicystic ameloblastomas. The deleterious action of this fixative on nerves has been studied but no attention has been paid to its effects on nearby vessels. The aim of this study was to investigate the effects of Carnoy's solution on blood vessels. The rat axillary artery and vein were surgically exposed, soaked with Carnoy's solution and kept in place for 2, 5 or 10 min, depending on the treatment group. The 5-min group was followed for 1, 2 and 3 weeks postoperatively. The vessels in the 2-min and 5-min exposure groups showed histological changes to the vessels, represented by focal loss of the endothelium and hyalinization of the wall. These alterations increased in the 10-min group. The vessels in the 3-week observation period revealed signs of recovery. It is concluded that Carnoy's solution can damage blood vessels but the process is reversible for exposure times less than 5 min.

Management of subclavian and axillary artery injuries: spanning the range of current therapy.

Injuries of the subclavian and proximal axillary arteries are potentially devastating but account for a minority of vascular injuries presenting to trauma centers in the United States. We have reviewed our recent experience with management of subclavian and axillary artery injuries in a state-designated level 1 academic trauma center and report four cases that illustrate the typical arterial injury patterns and the entire therapeutic armamentarium in its current iteration. Subclavian and proximal axillary artery injuries present as interesting surgical problems. A high index of suspicion for vascular injuries should be maintained given the mechanism and proximity to major vasculature. Consideration should always be given to the least invasive treatment options in stable patients. Awareness of multiple therapeutic modalities and indications for each should be an integral part of every surgeon's armamentarium. As with all vascular intervention, eventual failure is the rule rather than the exception; therefore, plans for longitudinal surveillance should be made independent of the technique used to treat the injury.

Oral contraceptives and vascular reactivity of great vessels in women.

Blood pressure and great vessel vascular reactivity, evaluated by color Doppler ultrasound, were investigated in users of third-generation oral contraceptives (n = 18) compared to non-users, who were studied either in the follicular (n = 8) or in the luteal (n = 10) phase of the menstrual cycle. Blood pressure measured at rest in the supine position, evaluated both in the follicular phase and in the luteal phase, was similar between oral contraceptive users and non-users. The pulsatility index (an indirect index of resistance to blood flow) of both the internal carotid artery and the axillary artery was similar in control women studied in the follicular phase and in the luteal phase. By contrast, in users of oral contraceptives, pulsatility index values of the internal carotid artery tended to be higher, whilst those of the axillary artery were significantly higher, than those of women in either the follicular phase (p < 0.01) or the luteal phase (p < 0.025). In conclusion, new third-generation oral contraceptives do not have a significant impact on blood pressure control, but still tend to increase vascular resistance to blood flow, particularly in areas more involved in the regulation of blood pressure, for example the axillary artery.

Characterization of the specific response to serotonin of mouse tumour-feeding arterioles.

PURPOSE: To investigate the role of tumour versus non-tumour factors in the specific response to serotonin (5-HT) of tumour-feeding arterioles (TFA). MATERIALS AND METHODS: Using mouse models of intra-vital microscopy, the response to topical administration of 5-HT was studied in arterioles feeding tumours: fibrosarcoma (Meth A), murine mammary adenocarcinoma (EMT6) and human colo-rectal carcinoma (HRT18) intra-cutaneously implanted. RESULTS: For all types of tumour, 5-HT induced a far more pronounced constriction of TFA than of control arterioles. The presence of a tumour implanted in the connective tissue between the skin and the cremaster muscle also affected the reactivity of muscle arterioles. Conversely, the response to serotonin by neovessels grown after implantation of an exogenous element under the skin did not differ from that of control arterioles. CONCLUSIONS: Changes in reactivity to serotonin were not dependent on the type of tumour implanted in the skin and were not present for a non-tumour implant. The presence of the tumour can alter the reactivity of vessels from tissue in contact with the tumour even if these vessels did not feed the tumour. This phenomenon is local and was not found in the vessels at a distance from the tumour.

Influences of melatonin administration on the circulation of women.

The cardiovascular effects induced by the daytime administration of melatonin (1 mg) were compared with those of placebo in 17 young, healthy, early follicular-phase women. Compared with placebo, the administration of melatonin modified, within 90 min, the pulsatility index (PI), evaluated by color Doppler ultrasound, of the internal carotid artery, abdominal aorta, and axillary artery. The effect was linearly related to baseline PI, higher baseline PI being associated with greater PI declines. Melatonin administration significantly decreased mean PI of internal carotid artery (P < 0.02), systolic and diastolic blood pressure (P < 0.01), and norepinephrine levels evaluated after 5 min of standing position (P < 0.02). Heart rate and supine catecholamine levels were not modified. These data indicate that in young, healthy women the administration of 1 mg of melatonin greatly influences artery blood flow, decreases blood pressure, and blunts noradrenergic activation. Clinical implications of present data are worthy to be fully explored.

Distribution of neurally activated postjunctional adrenoceptors in cat forelimb vasculature.

We assessed the relative contribution of postjunctional alpha-adrenoceptor subtypes in neurally evoked vasoconstrictor responses in the forelimb of anesthetized cats. Preganglionic stimulation of the thoracic sympathetic nerve trunk produced frequency-related decreases in blood flow of the entire forelimb as measured by ultrasonic flowmetry as well as vasoconstriction in the digital cutaneous bed as measured by laser-Doppler flowmetry. Vasoconstrictor responses were not altered significantly by intravenous (i.v.) treatment with propranolol (1 mg/kg) or atropine (1 mg/kg). In the entire limb, prazosin, (3-100 micrograms/kg i.v.) was a more potent antagonist of neurally evoked responses as compared with rauwolscine. In contrast, rauwolscine (10-300 micrograms/kg i.v.) was a more effective antagonist in the cutaneous bed. Combined treatment with both prazosin and rauwolscine was far more effective than either antagonist given alone in blocking vasoconstriction regardless of the measurement site. Moreover, basal cutaneous blood flow was increased by rauwolscine but not by prazosin. These results suggest that both subtypes of postsynaptic alpha-adrenoceptors are activated by sympathetic nerve stimulation. In the cutaneous bed, alpha 2-adrenoceptors appear to predominate. In addition, cutaneous vascular tone also appears to be regulated by hormonal alpha 2-adrenoceptor activation in cats.

Brachial plexus anesthesia and axillary sheath elastance.

Large volumes of an anesthetic solution used during regional axillary anesthesia may produce elevated pressures within the axillary sheath that lead to arterial compression and diminished blood flow. We measured axillary sheath pressure as a function of injected volume in 20 patients scheduled for hand surgery. Bupivacaine without epinephrine was injected into the axillary sheath in 10-ml increments until a cumulative volume of 50 ml was attained. Elastance (delta P/delta V), where delta P equals change in pressure (mm Hg) and delta V equals change in volume (ml), was 0.8 +/- 0.1 (+/- SEM) mm Hg/ml in successful block and 0.09 +/- 0.1 mm Hg/ml in unsuccessful blocks. Axillary sheath pressure did not exceed mean arterial pressure for periods longer than 60 s. We conclude that vascular insufficiency resulting from arterial compression following axillary block anesthesia is unlikely.