Medial Elastic Fibers Research Articles

Elastic tissue disruption is a major pathogenic factor to human vascular disease.

Elastic fibers are essential components of the arterial extracellular matrix. They consist of the protein elastin and an array of microfibrils that support the protein and connect it to the surrounding matrix. The elastin gene encodes tropoelastin, a protein that requires extensive cross-linking to become elastin. Tropoelastin is expressed throughout human life, but its expression levels decrease with age, suggesting that the potential to synthesize elastin persists during lifetime although declines with aging. The initial abnormality documented in human atherosclerosis is fragmentation and loss of the elastic network in the medial layer of the arterial wall, suggesting an imbalance between elastic fiber injury and restoration. Damaged elastic structures are not adequately repaired by synthesis of new elastic elements. Progressive collagen accumulation follows medial elastic fiber disruption and fibrous plaques are formed, but advanced atherosclerosis lesions do not develop in the absence of prior elastic injury. Aging is associated with arterial extracellular matrix anomalies that evoke those present in early atherosclerosis. The reduction of elastic fibers with subsequent collagen accumulation leads to arterial stiffening and intima-media thickening, which are independent predictors of incident hypertension in prospective community-based studies. Arterial stiffening precedes the development of hypertension. The fundamental role of the vascular elastic network to arterial structure and function is emphasized by congenital disorders caused by mutations that disrupt normal elastic fiber production. Molecular changes in the genes coding tropoelastin, lysyl oxidase (tropoelastin cross-linking), and elastin-associated microfibrils, including fibrillin-1, fibulin-4, and fibulin-5 produce severe vascular injury due to absence of functional elastin.

Inhibition of transforming growth factor-β signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome.

Increased transforming growth factor-β (TGF-β) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-β type II receptor gene Tgfbr2 in myeloid cells of Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) and evaluated macrophage infiltration and TGF-β signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO mice, both canonical and noncanonical TGF-β signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-β enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-β signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.

Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis.

Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo. We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. We prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRβ (platelet-derived growth factor receptor β). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD (Lactobacillus casei cell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction upon Lactobacillus casei cell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRβ inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in <5-year-old. This provides a basis for coronary pathology susceptibility in this very young cohort. Platelet-derived miR-223 (through PDGFRβ inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRβ represents potential therapeutic strategies to alleviate coronary pathology in KD. Graphic Abstract: A graphic abstract is available for this article.

Remodeling of the pulmonary artery in idiopathic pleuroparenchymal fibroelastosis

Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare subtype of idiopathic interstitial pneumonia that consists of alveolar septal elastosis and intra-alveolar collagenosis, which is predominantly located in the upper lobes. The aim of this study was to examine the remodeling of the pulmonary arteries in patients with IPPFE. This study included 18 patients with IPPFE, 24 patients with idiopathic pulmonary fibrosis (IPF), and 5 patients without pulmonary disease as controls. We selected muscular pulmonary arteries and calculated the percentage of the thickness of each layer of the wall (intima, media, and adventitia) in relation to the external diameter. We also quantified the percentage of areas of elastic fiber in the media divided by the whole area of the media (medial elastic fiber score). The percentage of adventitial thickness in IPPFE was significantly higher than that in IPF and in control lungs. The percentage of medial thickness did not differ statistically between IPPFE and IPF. However, the medial elastic fiber score in IPPFE was also significantly larger than that in IPF and control lungs. These results suggest that collagenous thickening of the adventitia and medial elastosis are distinct histological features in the muscular pulmonary arteries of patients with IPPFE.

1440Anti-inflammatory adipokine, omentin, attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein-E knockout mice

Abstract Background Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity is associated with an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated by obesity. Recently we have demonstrated that omentin is an anti-inflammatory adipokine that prevents the development of atherosclerosis in apolipoprotein-E knockout (apoE-KO) mice. Here we examined whether omentin could modulate angiotensin II-induced AAA formation in apoE-KO mice. Methods and results To overexpress human omentin in apoE-KO mice, apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue under the control of AP2 promoter (OMT-Tg mice). Circulating levels of human omentin in apoE-KO/OMT-Tg mice were approximately threefold higher than those in healthy human subjects, whereas human omentin was undetectable in apoE-KO mice. There were no differences in body weight, blood pressure and heart rate between apoE-KO/OMT-Tg and apoE-KO mice. We also subjected apoE-KO/OMT-Tg and apoE-KO mice at 24 weeks of age to continuous angiotensin II-infusion by using osmotic mini pumps for 4 weeks, which is a widely-accepted model of experimental AAA. ApoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA determined by direct measurement and ultrasound imaging as compared with apo-E KO mice. In histological analyses with van Gieson staining, apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibers in response to angiotensin II compared with apo-E KO mice. ApoE-KO/OMT-Tg mice also displayed reduced mRNA levels of matrix metalloproteinase (MMP) 2 and MMP9 as well as pro-inflammation genes including interleukin (IL)-6 in aortic walls compared with apo-E KO mice. Treatment of human monocyte-derived macrophages with human omentin protein attenuated LPS-stimulated expression of MMP9, TNF-α and IL-6. Omentin treatment also reduced LPS-induced activation of MMP9 in cultured media of human macrophages as evaluated by gelatinolytic zymography. Omentin treatment increased phosphorylation levels of Akt in human macrophages. The suppressive effects of omentin on inflammatory response in macrophages were reversed by treatment with LY294002, which is an inhibitor of PI3 kinase/Akt signaling. Conclusion These data suggest that omentin acts as an adipokine that can attenuate angiotensin II-induced development of AAA through suppression of MMP activation and inflammatory response in the vascular wall.

Characteristics of Adults Having Aortic Valve Replacement for Pure Aortic Regurgitation Involving a Congenitally Bicuspid Aortic Valve Unaffected by Infective Endocarditis or Aortic Dissection

Few reports have appeared describing patients with a purely regurgitant congenitally bicuspid aortic valve (BAV) unassociated with active or healed infective endocarditis or with acute or healed aortic dissection. This report describes a large group of such patients who had replacement of the purely regurgitant BAV with or without concomitant resection of the ascending aorta. Operatively excised purely regurgitant BAVs were examined and then their clinical records were examined to confirm that the valves indeed were purely regurgitant. The patients were aged 21 to 86 years (median 50). Of the 133 patients, 114 (86%) were men. The degree of aortic regurgitation (AR) ranged from 1+ to 4+/4+. Of the 133 patients, 52 (39%) had simultaneous resection of the ascending aorta, its frequency varying inversely with the degree of AR. Histologic study of sections of the operatively excised aortas disclosed that 28 (54%) had a normal or nearly normal aorta (0-1+ loss of medial elastic fibers) and that 24 (46%) had an abnormal loss (grade 2+ -4+/4+). In conclusion, the congenitally BAV, unassociated with either infective endocarditis or aortic dissection, is a common cause of pure AR in adults in the Western World undergoing AVR for AR. About half the patients had a dilated ascending aorta and those resected were histologically abnormal half the time. Why one BAV becomes stenotic, another purely regurgitant, another the site of infective endocarditis, and another functions normally for an entire lifetime remains unclear.

Hybrid Reconstruction of the Aortic Arch Using a Double-Branched Stent-Graft in a Canine Model

ABSTRACTPurpose: To report the results of a hybrid approach to aortic arch repair using an innovative unibody double-branched stent graft in a canine model.Materials and methods: The stent-graft system consists of two parts: the main body and two branches for reconstruction of the supra-arch branches. There is a 2-cm-long suturing portion at the proximal end of the main body. Twenty adult German sheep dogs underwent a hybrid surgical treatment to place the stent-grafts into the proximal descending aorta and the supra-arch branches. Outcomes were assessed by operative mortality, complications, imaging studies, and histomorphometric analyses.Results: Placement of the stent-graft was performed successfully in all dogs without complications. One dog died of respiratory failure due to early extubation. The other dogs survived to 6 months without complications, at which time they were sacrificed. The mean cardiopulmonary bypass time was 80.3 ± 7.3 mins and hypothermic circulatory arrest time was 10.7 ± 1.9 min. The average blood loss was 373.5 mL. At 6 months, postoperative aortic imaging indicated that the main body and branches of the stent-graft were fully open and in satisfactory position. No migration, deformation, or endovascular leakage was observed. Histomorphometric results showed normal arrangement of medial and adventitial elastic fibers, moderately proliferated intima, with or without neo-microvessels, and microscopic morphological changes in internal elastic lamina.Conclusions: These results demonstrate that it is possible and safe to reconstruct the aortic arch with the novel open-branched stent-graft placement.

Surgical Treatment of Pulmonary Complications in Behçet's Syndrome

We described disease characteristics, management and outcome of a group of Behçet's syndrome (BS) patients who underwent pulmonary lobectomy, segmentectomy or various pleura interventions for complications due to pulmonary artery or descending aorta involvement. There were 9 patients with BS (8 M/1 F; mean age: 24.8 ± 7.5 and mean disease duration: 4.3 ± 3.8 years) who underwent lung surgery from 2000 to 2017. Their medical files including operation details and radiological and pathological studies were reviewed retrospectively. Lobectomy was done in 6 patients, decortications and pleura interventions in the remaining 3. The reason for the surgical procedures were giant pulmonary arterial aneurysms refractory to the medical treatment (n = 4), pneumothorax due to large cavities (n = 2), pleural effusions refractory to the medical treatment (n = 1), a bronchopleural fistula after embolization (n = 1) and bronchiectasis (n = 1). All patients received medical treatment with cyclophosphamide and corticosteroids before the surgical interventions. The histological examination in patients with pseudo-aneurysms showed destruction of medial elastic fibers, inflammatory cell infiltration of adventitial tissues and penetration into the adjacent bronchi with adherent thrombi. Two patients died: one due to Budd-Chiari syndrome 1 year after the surgery, another because of a massive hemoptysis 3 months after lobectomy. The remaining 7 patients are still alive with a median follow-up of 8 years (inter-quartile range [IQR]: 4-11). Lobectomies in BS patients with giant pulmonary aneurysms refractory to medical treatment can be done with favorable outcome. Also, complications such as large cavities causing pneumothorax, refractory pleural effusions, bronchiectasis, and embolization complications can be managed effectively with surgical interventions.

High-pressure intraarterial injection for establishing animal model of traumatic skull base artery injury

Objective To evaluate the animal model of traumatic skull base artery injury (TSBAI) established by the high-pressure intraarterial injection method. Methods Fifty New Zealand rabbits were submitted to high-pressure carotid artery injection (experiment group, n=20), tension-free carotid artery injection (sham group, n=20) and simple carotid artery exposure (control group, n=10), according to the random number table. Animal survival was observed. Diameters of carotid artery were measured using the CT angiography (CTA). Pathological changes of the involved carotid artery were monitored under microscope. Results There were three deaths in experiment group, with the success rate of modeling of 85%. There were two deaths in sham group. All animals in control group survived. Diameter of right carotid artery at postoperative one week was (1.62±0.10)mm in experiment group, reduced compared to (2.25±0.08)mm in sham group and (2.43±0.15)mm in control group (P<0.05). For experiment group, intimal tear, loss of normal continuity, and local platelet thrombus formation attaching to the vascular intimal tear were observed in the injured right carotid artery, medial elastic fibers showed structural disorder complicated with discontinuous fibers, and deposition of red blood cells, lymphocytes and macrophages were observed. Conclusions High-pressure intraarterial injection for induction of the TSBAI model is associated with maneuverable operation, low risk, few complications and morphological results conforming to the actual damage. The model can survive for a long time that is suitable for investigating the pathological and physiological mechanism of traumatic skull base artery full-thickness injury and the legacy effect. Key words: Cerebrovascular trauma; Carotid arteries; Skull base; Rabbit

The Effects of Losartan in Preserving the Structural Integrity of Decellularized Small Diameter Vascular Allograft Conduit Implants In Vivo.

Decellularization is a proposed method of preparing nonautologous biological arterial vascular scaffolding; however, the fate of the supporting medial elastic fiber, which is important in preserving the vascular structural integrity, is uncertain. The influence of losartan on preserving the medial elastic fiber integrity in decellularized small diameter vascular conduits (SDVC) was investigated. Decellularized infrarenal abdominal aortic allografts were implanted in Sprague-Dawley rats treated either with (study rats, n = 6) or without oral losartan (control rats, n = 6) and graded 8 weeks later according to a remodeling scoring system (1-mild, 2-moderate, 3-severe) which we devised based on the intimal hyperplasia degree, morphologic changes, and elastic fiber fragmentation of the conduits. DAPI immunohistochemistry analysis was performed in 47 (25 decellularization only and 22 losartan treatment) cross-sectional slide specimens. The losartan versus decellularization only SDVC showed a significantly lower medial elastic fragmentation score (1.32 vs. 2.24, P < 0.001), superior medial layer preservation, and relatively more normal appearing intimal cellular morphology. The results suggested rats receiving decellularized SDVCs treated with losartan may yield superior medial layer elastic fiber preservation.

Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice.

The precise role of smooth muscle cell contractility in elastic arteries remains unclear, but accumulating evidence suggests that smooth muscle dysfunction plays an important role in the development of thoracic aortic aneurysms and dissections (TAADs). Given the increasing availability of mouse models of these conditions, there is a special opportunity to study roles of contractility ex vivo in intact vessels subjected to different mechanical loads. In parallel, of course, there is a similar need to study smooth muscle contractility in models that do not predispose to TAADs, particularly in cases where disease might be expected. Multiple mouse models having compromised glycoproteins that normally associate with elastin to form medial elastic fibers present with TAADs, yet those with fibulin-5 deficiency do not. In this paper, we show that deletion of the fibulin-5 gene results in a significantly diminished contractility of the thoracic aorta in response to potassium loading despite otherwise preserved characteristic active behaviors, including axial force generation and rates of contraction and relaxation. Interestingly, this diminished response manifests around an altered passive state that is defined primarily by a reduced in vivo axial stretch. Given this significant coupling between passive and active properties, a lack of significant changes in passive material stiffness may help to offset the diminished contractility and thereby protect the wall from detrimental mechanosensing and its sequelae.

Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.

Pulse pressure relation to aortic and left ventricular structure in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study.

High pulse pressure, a major cardiovascular risk factor, has been attributed to medial elastic fiber degeneration and aortic dilation, which transfers hemodynamic load to stiffer collagen. However, recent studies suggest higher pulse pressure is instead associated with smaller aortic diameter. Thus, we sought to elucidate relations of pulse pressure with aortic stiffness and aortic and cardiac dimensions. We used magnetic resonance imaging to examine relationships of pulse pressure with lumen area and wall stiffness and thickness in the thoracic aorta and left ventricular structure in 526 participants (72-94 years of age, 295 women) in the community-based Age, Gene/Environment Susceptibility-Reykjavik Study. In a multivariable model that adjusted for age, sex, height, weight, and standard vascular risk factors, central pulse pressure had a negative relationship with aortic lumen area (all effects expressed as mm Hg/SD; B=-8.1±1.2; P<0.001) and positive relationships with left ventricular end-diastolic volume (B=3.8±1.0; P<0.001), carotid-femoral pulse wave velocity (B=3.6±1.0; P<0.001), and aortic wall area (B=3.0±1.2; P=0.015). Higher pulse pressure in older people is associated with smaller aortic lumen area and greater aortic wall stiffness and thickness and left ventricular volume. Relationships of larger ventricular volume and smaller aortic lumen with higher pulse pressure suggest mismatch in hemodynamic load accommodation by the heart and aorta in older people.

Abstract 114: Macrophages Mediate the Ability of the Receptor for Advanced Glycation End Products to Prevent Formation of Abdominal Aortic Aneurysm in a Murine Model

INTRODUCTION: The pathophysiology of AAAs is multifactorial, involving chronic inflammation, increased MMP expression/activity, and medial elastic fiber destruction. RAGE transduces the biological impact of ligand families including AGEs, S100, and HMGB1 to upregulate inflammatory and tissue injury-provoking genes including MMPs. We previously identified increased RAGE expression in human AAAs and have shown that the absence of RAGE, whether by genetic deletion or pharmacologic blockade with sRAGE, prevents AAA formation in a mouse model. We sought to characterize the cellular mediators of this effect. METHODS: C57BL/6 wild-type (WT) and RAGE null (KO) mice underwent transient elastase perfusion to induce AAAs. Mice were sacrificed at day 14 and flow cytometry performed to characterize differences in activation (CD69+) of lymphocytes (CD4/8), neutrophils (GR1+/CD11b+), macrophages (F480), NK cells (NK1.1) (n=24/group). Immunohistochemistry was performed for Mac-3 and Arg 1 (M2 marker) or Arg 2 (M1 marker). Primary BMDMs were isolated and skewed towards M1 (LPS/IFN ¡) or M2 (LPS, IL-4, IL-13) with the addition of S100b or HMGB1 to determine the ligands' effect upon macrophage skewing by ELISA. RESULTS: Flow cytometry revealed increased aortic expression of activated CD8+ cells (p=0.002), macrophages (p-0.002), and NK cells (p=0.03). No differences were noted in cellular activation from spleens from the same animals. Immunohistochemistry revealed increased macrophage expression in WT vs KO aortae, highest at day 5 (p=0.04). Arg 1 and 2 expression on macrophages was elevated in WT vs KO animals (p=0.03). Skewing BMDMs from WT and KO towards M1 led to elevated TNFα with addition of either S100b (p=0.02) or HMGB1 (p=0.03). Skewing BMDMs towards M2 led to elevated IL-10 in KO vs WT cells with the addition of S100b (p=0.01). HMGB1 has no effect upon skewing towards M2. CONCLUSIONS: The effect of RAGE in the development of murine AAA appears to be mediated by macrophages. Differential macrophage skewing towards an M1 by both S100b and HMGB1 likely plays a role in this effect. Skewing towards M2 is mediated by S100b and not HMGB1. Further studies will seek to identify at which stage in AAA formation activation of the RAGE-ligand axis becomes functionally important.

Late aneurysm formation of Valsalva sinus after aortic valve replacement due to Takayasu’s arteritis

Takayasu's arteritis (TA) is an inflammatory disease of unknown etiology involving the aorta and its branches, and also causes aortic regurgitation (AR). One of the most serious but rare complications after aortic valve replacement (AVR) in TA is aneurysm formation of the sinus of Valsalva. A 64-year-old woman had undergone AVR with a prosthetic valve for AR due to TA 4years earlier and had received an implanted permanent pacemaker for complete atrioventricular block (AVB) 2years later. Aortography 4years postoperatively demonstrated aneurysm formation (47mm in diameter) at the sinus of Valsalva although preoperative aortography showed severe AR without dilatation of the sinus of Valsalva. We recommended reoperation for the aneurysm but the patient refused. The perioperative histopathological examination revealed extensive destruction of the medial elastic fibers. Both the fragility of the sinus of Valsalva and the residual inflammation could have caused the patient's aneurysm formation. Moreover, extension of TA into the ventricular septum or mechanical compression of the aneurysm against the conduction system might have caused her progressive AVB. Close and lifelong follow-up for patients with TA regarding development of aneurysm after surgical treatment is indispensable when fragility of the aortic root had been confirmed.

Abstract 512: Angiotensin II Type 1 Receptor is Essential for the Initiation and Progression of Porcine Pancreatic Elastase-Induced Experimental Abdominal Aortic Aneurysms

Angiotensin (Ang) II type 1 receptor (AT1) activity is critical for experimental abdominal aortic aneurysm (AAA) formation in response to Ang infusion in hyperlipidemic mice. The role of AT1 activity in exogenous Ang II-independent, experimental AAA is unknown. Genetic and pharmacological inhibition strategies were used to isolate the significance of AT1 function in porcine pancreatic elastase (PPE)-induced AAAs in normolipidemic C57BL/6 mice. AAA progression was monitored via serial in-vivo transabdominal ultrasound measurements at 40 mHz. Aortic diameters enlarged remarkably from day 3 to day 14 in control mice following PPE infusion. Progression was abrogated, however, following either targeted AT1a receptor deletion, or treatment with the AT1 inhibitor telmisartan, beginning day 3 prior to PPE infusion. Additionally, telmisartan treatment initiated 4 days following PPE-infusion led to stabilization /regression of existing AAAs. Histologically, AT1a deficiency or telmisartan treatment resulted in preserved medial smooth muscle cellularity and elastic fibers, and attenuated mural angiogenesis and leukocyte infiltration. Telmisartan treatment did not affect PPARγ-regulated gene expression in aneurysmal aortae, however, and the PPARγ antagonist (GW9662) did not influence telmisartan-induced AAA suppression. In conclusion, AT1 activity is required for the initiation and progression of experimental AAAs, independent of the specific methodology used to induce aneurysm formation. Strategies targeting AT1 activity may prove effective in limiting human AAA progression.

Surgical correction of giant extracardiac unruptured aneurysm of the right coronary sinus of Valsalva: case report and review of the literature

We report a quite rare case of giant extracardiac unruptured aneurysm of the right coronary sinus of Valsalva with no clinical findings of Marfan syndrome or Ehlers-Danlos syndrome. A 52-year-old Chinese male was diagnosed having an aneurysm of the right sinus of Valsalva and moderate aortic regurgitation, while Bentall operation was performed successfully. The patient was discharged with no complications. Pathological examination revealed conspicuously medial mucoid degeneration of the aneurismal wall and absence of medial elastic fibers. Immediate results and early follow-up were uneventful.

Aortic Root Reimplantation for Isolated Sinus of Valsalva Aneurysm in the Patient With Marfan's Syndrome

We describe an isolated extracardiac unruptured acquired aneurysm in the right coronary sinus of Valsalva, which was seen in a 55-year-old woman with Marfan's syndrome. The patient underwent aortic root replacement using a reimplantation technique. Pathologic examination revealed absence of the medial elastic fiber of the aortic wall of the normal sinus of Valsalva. This result supports the preference of entire root replacement instead of patch repair of the affected sinus for the isolated aneurysm in 1 sinus of Valsalva in a patient with Marfan's syndrome.

Aortic Medial Elastic Fiber Loss in Acute Ascending Aortic Dissection

Aortic Medial Elastic Fiber Loss in Acute Ascending Aortic Dissection

Characteristics of TAV- and BAV-associated thoracic aortic aneurysms—Smooth muscle cell biology, expression profiling, and histological analyses

Objective Past studies on the pathogenesis of thoracic aortic aneurysms have, by concentrating on histological and total tissue analyses, revealed several disease-relevant processes. Despite these studies, there is still a significant lack in the understanding of aneurysmal cell biology today. Hence, it was the goal of this study to assess differences between aneurysmal and healthy aortic smooth muscle cells (SMCs) on a broad – screening-like – basis, allowing us to formulate new hypotheses on the role of SMCs in thoracic aneurysm formation. Methods and results After histological characterization of a total of 16 samples from healthy aortas and thoracic aortic aneurysms (TAA) of patients with bicuspid (BAV) and tricuspid (TAV) aortic valves, we isolated aortic SMCs and subjected them to cell biological and gene expression analyses. The data obtained indicate that aneurysmal SMCs exert reduced proliferation and migration rates compared to controls. BAV TAA SMCs have significantly shorter telomeres, whereas TAV TAA SMCs showed a reduced metabolic activity. In BAV TAA SMCs osteopontin (OPN) expression was significantly elevated, and TAV TAA SMCs showed decreased expression of tissue inhibitor of metalloproteinase 3 (TIMP3). Conclusion Our study provides evidence that TAA-associated aortic wall disintegration in BAV and TAV TAAs shows similarities, but also significant differences. BAV and TAV TAAs differ with regard to medial elastic fiber mass and the occurrence of fibroblasts, SMC telomere length, metabolism, and gene expression. This study may form the basis for future in-depth analyses on the relevance of these findings in the pathophysiology of BAV and TAV TAAs.