Abdominal aortic aneurysms are characterized by chronic inflammatory cell infiltration. AAA is typically an asymptomatic disease and caused approximately 15,000 deaths annually in the U.S. Previous studies have examined both human and murine aortic tissue for the presence of various inflammatory cell types. Studies show that in both human and experimental AAAs, prominent inflammatory cell infiltration, such as CD4+ T cells and macrophages, occurs in the damaged aortic wall. These cells have the ability to undergo phenotypic modulation based on microenvironmental cues, potentially influencing disease progression. Pro-inflammatory CD4+ T cells and classically activated macrophages dominate the landscape of aortic infiltrates. The skew to pro-inflammatory phenotypes alters disease progression and plays a role in causing chronic inflammation. The local cytokine production and presence of inflammatory mediators, such as extracellular matrix breakdown products, influence the uneven balance of the inflammatory infiltrate phenotypes. Understanding and developing new strategies that target the pro-inflammatory phenotype could provide useful therapeutic targets for a disease with no current pharmacological intervention.
Stress or cocaine evokes either a large increase in systemic vascular resistance (SVR) or a smaller increase in SVR accompanied by an increase in cardiac output (designated vascular and mixed responders, respectively) in Sprague-Dawley rats. We hypothesized that the central nucleus of the amygdala (CeA) mediates this variability. Conscious, freely-moving rats, instrumented for measurement of arterial pressure and cardiac output and for drug delivery into the CeA, were given cocaine (5 mg/kg, iv, 4-6 times) and characterized as vascular (n=15) or mixed responders (n=10). Subsequently, we administered cocaine after bilateral microinjections (100 nl) of saline or selective agents in the CeA. Muscimol (80 pmol), a GABA A agonist, or losartan (43.4 pmol), an AT 1 receptor antagonist, attenuated the cocaine-induced increase in SVR in vascular responders, selectively, such that vascular responders were no longer different from mixed responders. The corticotropin releasing factor (CRF) antagonist, α-helical CRF 9-41 (15.7 pmol), abolished the difference between cardiac output and SVR in mixed and vascular responders. We conclude that greater increases in SVR observed in vascular responders are dependent on AT 1 receptor activation and, to a lesser extent on CRF receptors. Therefore, AT 1 and CRF receptors in the CeA contribute to hemodynamic response variability to intravenous cocaine.
Objective: Abundant evidence has demonstrated the profound influence of genetic background on cardiovascular phenotypes. Previous work in the mouse has shown that genetic background-related variations in murine models of Marfan syndrome affect thoracic aortic aneurysm formation, rupture, and lifespan of mice. Marfan syndrome mice in the C57Bl/6 genetic background are less susceptible to aneurysm formation compared to 129/SvEv mice. In this study, we hypothesize that the susceptibility to the development of abdominal aortic aneurysm (AAA) will be similarly increased in 129/SvEv mice compared to C57Bl/6 mice. Approach and Results: Mice of either C57Bl/6 or 129/SvEv background underwent AAA induction by periaortic application of CaCl2. Aortic diameters were measured at 6 weeks post induction. Aneurysm size was significantly larger in 129/SvEv mice than in C57Bl/6 mice. Histological studies showed more severe elastic lamella disruption and fragmentation in 129/SvEv mice than in C57Bl/6 mice. Macrophage infiltration was more prominent in the aortas of 129/SvEv mice than of C57Bl/6 mice. The elastic modulus was found to be higher in the aortas of the 129/SvEv mice compared to the C57Bl/6 mice. MMP-2 and MMP-9 levels, examined by gelatin zymography,were higher in the aortas of 129/SvEv mice compared to the C57Bl/6 mice. Conclusions: These data demonstrate that 129/SvEv mice are more susceptible to AAA compared to C57Bl/6 mice. The difference in the susceptibility to AAA is at least partially due to the difference in aortic elastic lamellae mechanical properties and MMP-2 and -9 expression between the two strains of mice.
Objective: Abdominal aortic aneurysm (AAA) is a disease characterized by inflammatory cell infiltration and extracellular matrix (ECM) degradation. Damage to the ECM results in release of elastin-derived peptides (EDPs). EDPs recruit inflammatory cells and may influence macrophage polarization. BA4, a monoclonal antibody that specifically recognizes a six peptide sequence in EDPs, can block the EDP-mediated effect on macrophages. Our hypothesis is that EDPs induce M1 differentiation and that blocking the EDP-mediated M1 differentiation of macrophages will reduce aneurysm progression. Methods: Mice were given weekly intraperitoneal injections of BA4 (10 mg/kg) or IgG (10 mg/kg) after aneurysm induction via the calcium chloride (CaCl2) induced aneurysm model. Aortic tissue was then removed and subjected to Western blot, gelatin zymography, and histological analysis at various time points (3 days, 1, 2, 4, and 6 weeks) after aneurysm induction. Bone marrow-derived macrophages (BMMs) were isolated and treated with various doses of EDPs and their gene expression profiles were analyzed by qPCR. Additionally, BMMs were treated with IFN-γ to induce a pro-inflammatory M1 phenotype or IL-4 to induce an anti-inflammatory M2 phenotype. M1 or M2 BMMs were given intravenously to mice, which then underwent aneurysm induction. Results: BA4 treatment significantly reduced aortic dilation, ECM degradation, and macrophage infiltration. EDP treatment of naïve macrophages induced a response similar to IFN-γ resulting in M1 activation as seen by expression of M1 associated markers such as TNF-α and IL-1β. Additionally, administration of M1 polarized BMMs to CaCl2-treated mice significantly increased aortic dilation compared to administration of M2 polarized BMMs. Conclusions: EDPs cause a pro-inflammatory M1 response similar to that seen with IFN-γ treatment. Reducing the M1 response by inhibition of EDP-mediated signaling or administration of M2 polarized BMMs reduces aneurysm formation. Targeting the macrophage phenotype is a potential therapeutic target for AAA.
Objectives: Abdominal aortic aneurysm (AAA) is a chronic disease characterized by persistent inflammation maintained by an array of inflammatory cells and mediators. Interleukin 1 beta (IL-1β) has largely been considered a pro-inflammatory cytokine but, interestingly, our previous studies of human AAAs showed that activated T-cells from patients with AAAs expressed lower levels of IL-1β compared to matched control patients without AAAs. This led us to hypothesize that IL-1β could have a protective role in preventing the development of AAA. Methods: Abdominal aortic aneurysms were induced in IL-1 receptor KO (IL-1R -/- ) and control mice using the CaCl 2 murine model of AAA. Mice were sacrificed six weeks after aneurysm induction. Aortic diameters were measured and compared at the time of aneurysm induction and sacrifice. Aortic samples were further evaluated histologically using connective tissue staining to assess the aortic structure in both groups. Results: At the time of sacrifice, IL-1R -/- mice demonstrated a 73.9 ± 3.3% increase in aortic diameter compared to a 25.9 ± 5.8% increase in wild type control mice (p<0.05). On histology, IL-1R -/- mice had more severe disruption of the aortic architecture compared to control mice. These data suggest that in the absence of IL-1β signaling, mice are more susceptible to aneurysms and develop more severe pathology. Conclusion: The current mouse data, in combination with our previous human studies, suggest a protective role for IL-1β in abdominal aortic aneurysm. These results are unexpected given that related pro-inflammatory cytokines TNF-α and IFN-γ both promote aneurysm formation.
Introduction: Disease of the femoropopliteal artery (FPA) is associated with significant morbidity and quality of life impairment. End-stage lesions may be too advanced to determine how demographics and clinical risk factors impact arterial wall damage and lesion development; therefore we investigated the influence of these patient characteristics on various stages of human FPA histopathology. Methods: FPAs were obtained from 14-80 year-old human tissue donors ( n =120). Proximal segments of the arteries were mechanically tested and labeled with Verhoeff-Van Gieson stains. FPA intimal-medial damage severity was assessed and correlated with histology, mechanical properties, subject demographics, risk factors, and physiological stresses and stretches using Pearson correlation r with two-tailed significance levels. Results: Age correlated strongest ( r =0.664, p<0.01) with the degree of FPA intimal-medial damage, explaining 50% of the variation alone. Primarily due to medial calcification, more damaged FPAs were stiffer and demonstrated lower physiological circumferential stretch ( r =-0.510, p<0.01), circumferential stress and longitudinal stress ( r =-0.355, r =-0.379, p<0.01). More damage was associated with larger arterial radii ( r =0.470, p<0.01), thickened arterial walls ( r =0.238, p<0.01), decreased in situ longitudinal pre-stretch ( r =-0.537, p<0.01), less elastin in the arterial wall ( r =-0.432, p<0.01), thinner individual elastin fibers ( r =-0.571, p<0.01), and thinner, less dense, and more discontinuous external elastic laminae ( r =-0.252, r =-0.456, r =0.588, p<0.01). Damage was positively associated with male gender ( r =0.265, p<0.01), higher BMI ( r =0.224, p=0.01), hypertension ( r =0.266, p<0.01), diabetes ( r =0.265, p<0.01) and coronary artery disease ( r =0.375, p<0.01), but not with dyslipidemia ( r =0.117, p=0.161) or smoking history ( r =0.041, p=0.626). Conclusions: More severely damaged FPAs demonstrate elastin loss, medial calcification and increased stiffness compared to less damaged arteries. FPA damage correlates with most classical cardiovascular risk factors, but not with dyslipidemia or tobacco history, suggesting possible unique pathophysiological mechanisms that require further investigation.
The central nucleus of the amygdala (CeA) has been shown to play an important role in sympathetic and behavioral responses to stress. We observed a greater vasoconstrictor response to cocaine in some rats (vascular responders or VR) compared to other rats (mixed responders or MR). We hypothesized that the CeA was responsible for greater increases in systemic vascular resistance (SVR) in response to cocaine and that angiotensin II (Ang) and corticotropin‐releasing factor (CRF) receptors were involved. Rats were instrumented for arterial pressure and cardiac output determination and for drug microinjection into the CeA. Rats were given cocaine (5 mg/kg, iv, twice daily, 4X) to determine their response pattern (VR or MR). Subsequently, rats were pretreated with bilateral microinjections (100 nl) of saline, muscimol (80 pmol), losartan (20 ng), or á‐helical‐CRF9‐41 (60 ng) followed by cocaine. Pretreatment with muscimol or losartan attenuated the increase in systemic vascular resistance (SVR) evoked by cocaine. Pretreatment with CRF antagonist prevented the difference in responsiveness between MR and VR by increasing the increase in SVR in MR. Our data suggests that the greater increases in SVR in vascular responders depend on neuronal transmission in the CeA and that Ang receptors facilitate and CRF receptors inhibit SVR responses to cocaine administration. Supported by USPHS RO1 DA13256 and DA0017371.
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