Design and computational optimization of compliance-matching aortic grafts.

Introduction: Synthetic vascular grafts have been widely used in clinical practice for aortic replacement surgery. Despite their high rates of surgical success, they remain significantly less compliant than the native aorta, resulting in a phenomenon called compliance mismatch. This incompatibility of elastic properties may cause serious post-operative complications, including hypertension and myocardial hypertrophy. Methods: To mitigate the risk for these complications, we designed a multi-layer compliance-matching stent-graft, that we optimized computationally using finite element analysis, and subsequently evaluated in vitro. Results: We found that our compliance-matching grafts attained the distensibility of healthy human aortas, including those of young adults, thereby significantly exceeding the distensibility of gold-standard grafts. The compliant grafts maintained their properties in a wide range of conditions that are expected after the implantation. Furthermore, the computational model predicted the graft radius with enough accuracy to allow computational optimization to be performed effectively. Conclusion: Compliance-matching grafts may offer a valuable improvement over existing prostheses and they could potentially mitigate the risk for post-operative complications attributed to excessive graft stiffness.

Low-Intensity Electrostimulation Enhances Neuroregeneration and Improves Erectile Function in a Rat Model of Cavernous Nerve Injury.

BACKGROUND: Neurogenic erectile dysfunction (ED) following radical prostatectomy (RP) is a frequent complication often leading to erectile tissue remodeling and permanent ED. Low-intensity electrostimulation (LIES) has been shown to enhance peripheral nerve regeneration, however, its application on cavernous nerves (CN) has never been investigated. AIMS: To investigate whether LIES enhances CN regeneration, improves erectile function (EF) recovery, and prevents corpora cavernosal remodeling after CN injury, which is a principal factor for ED following RP. METHODS: Adult male Sprague-Dawley rats were divided into Sham, Bilateral Cavernous Nerve Injury (BCNI), and BCNI + LIES (1V, 0.1ms, 12Hz, 1h/day). After 7days, EF was assessed (ICP measurement). Penes and CN were collected for molecular analyses of TGF-ß1, Il-6, CRP, eNOS, ERK and AKT protein levels in corpus cavernosum (CC), and immunohistological analysis of DHE, total collagen and α-SMA in CC and S-100, Tub-III, DAPI, TUNEL, and nNOS in CN. OUTCOMES: Effects of LIES on EF, erectile tissue remodeling and CN structure. RESULTS: EF was decreased (P < .05) 7 days after BCNI and increased (P < .05) by LIES. Intracavernosal reactive oxygen species (DHE) was increased (P < .05) after BCNI and normalized by LIES. Protein expressions of TGF-ß1, IL-6, and CRP were increased in the penis (P < .05) after BCNI and normalized by LIES. The α-SMA and/or total collagen ratio was decreased (P < .05) after BCNI in the penis and normalized by LIES. Protein expression ratio of p-ERK/ERK and p-AKT/AKT did not change after BCNI but increased (P < .05) in LIES group. Myelination and number of nNOS positive cells in the CN were decreased (P < .05) after BCNI and normalized by LIES. The number of apoptotic nerve cells within the dorsal penile nerve was increased (P < .05) after BCNI and decreased (P < .05) by LIES compared to the BCNI group. There were no differences in eNOS expression in the penis between study groups. CLINICAL TRANSLATION: LIES may offer a potential new tool for penile rehabilitation and ED management following RP, potentially enhancing EF recovery and minimizing the side effects of this surgery. STRENGTHS & LIMITATIONS: This study provides evidence of the protective effect of LIES on EF and tissue remodeling following CN injury; nevertheless, this study has been conducted on animals and the translation to humans remains to be demonstrated. Further research to identify the underlying mechanisms of action is required. CONCLUSION: This study demonstrates that LIES of the CN after CN injury protects CN structure, enhances EF recovery, and prevents corpora cavernosal remodeling. Sturny M, Karakus S, Fraga-Silva R, et al. Low-Intensity Electrostimulation Enhances Neuroregeneration and Improves Erectile Function in a Rat Model of Cavernous Nerve Injury. J Sex Med 2022;19:686-696.

MRI after successful eyeWatchTM implantation.

The eyeWatchTM is a new glaucoma drainage device that includes an adjustable mechanism that can vary the resistance to aqueous humor outflow during the postoperative period to reduce the burden of postoperative intraocular pressure (IOP) management. The mechanism contains a magnetic rotor that can be adjusted using an external magnetic control unit. Adjustments of the position of the rotor are performed mostly in the initial postoperative follow-up period in order to reach the target IOP. However, for some patients, it might be necessary to perform MRI for the sake of medical investigations. As the MRI is creating a strong magnetic field, this magnetic field is likely to interact with the adjustable rotor of the eyeWatchTM, resulting in modification of the IOP. We report the case of an 82-old female patient successfully operated with the implantation of an eyeWatchTM. The patient underwent a cerebral MRI for persistent headache. Shortly after the MRI procedure, the patient was checked at the eye clinic to assess the position of the rotor and to measure the IOP. The eyeWatchTM was readjusted to the former position set before undergoing the MRI. No complications were reported in the follow-up after MRI. This case demonstrates that MRI examinations can be safely performed after glaucoma surgery using an eyeWatchTM without compromising on the quality of the imaging or the stability of the IOP. This is a complication-free procedure that only requires checking the new position of the rotor and re-adjusting the implant, if necessary, to achieve the target IOP.

Characterization of the Renin-Angiotensin System in Aged Cavernosal Tissue and its Role in Penile Fibrosis.

BACKGROUND: The renin-angiotensin system (RAS) plays an important role in erectile function. The RAS contains 2 major axes: one deleterious, composed of ACE-Ang II-AT1 receptor, and another protective, composed of ACE2-Ang-(1-7)-Mas receptor. While aging is a well-known cause for development of male sexual disorders, little is known about local regulation of the RAS in age-related erectile dysfunction (ED). AIM: The present study aimed to assess regulation of the RAS in aging-associated ED rat model and evaluate possible options for disease management through pharmacological modulation of the RAS. METHODS: Penile tissues were harvested from 3-, 12-, and 24-month-old Wistar rats. Local expression of major RAS components and ED markers was measured by RT-PCR. Protein expression of RAS components was assessed by western blot. Collagen deposition was measured by Sirius Red and immunohistochemical staining. Evaluation of collagen content was also performed in penile sections of Mas-knockout mice by Sirius Red and Masson's trichrome stainings. Finally, the effect of Ang-(1-7) pretreatment on TGF-ß-induced myofibroblast activation was studied in primary cavernosal and immortalized fibroblasts. OUTCOMES: Experimental results highlighted the essential role of the RAS in modulation of cavernosal fibrosis. RESULTS: The present study demonstrates local expression of angiotensinogen mRNA alongside with major RAS components, which suggests local autonomous functioning of the RAS within penile tissue. Gene expression analysis revealed strong positive correlation between ACE-Ang II-AT1 axis with markers for inflammation and fibrosis. While corpus cavernosum from 24-month-old rats was characterized by increased collagen deposition, protein expression of ACE, AT1, and Mas was shown to be upregulated in the penile tissue of this group. At the same time, penile sections from Mas-knockout mice (FVB/N background) were also shown to have increased collagen deposition. Finally, it was demonstrated that Ang-(1-7) treatment of primary cavernosal and immortalized fibroblasts was able to alleviate TGF-ß-induced fibroblast-to-myofibroblast transition. CLINICAL TRANSLATION: The present study suggests Ang-(1-7) treatment as a possible strategy for pharmacological management of fibrosis-associated ED in aging. STRENGTHS & LIMITATIONS: The link between the RAS and penile fibrosis, indicated by a holistic screening of different ED markers, was confirmed by in vivo and in vitro data. However, results, presented in the manuscript, need to be further reinforced by human data. Important to note, the main goal of the study was to characterize RAS regulation in aging condition rather than state any causal relationships. CONCLUSION: Present study characterizes RAS regulation in aging-associated ED and indicates its important role in cavernosal fibrosis. Bragina ME, Costa-Fraga F, Sturny M, et al. Characterization of the Renin-Angiotensin System in Aged Cavernosal Tissue and its Role in Penile Fibrosis. J Sex Med 2020;17:2129-2140.

Comparison Between the eyeWatch Device and the Ahmed Valve in Refractory Glaucoma.

PURPOSE: To assess the efficacy and safety of a glaucoma procedure to control intraocular pressure (IOP) using the adjustable eyeWatch glaucoma drainage device compared with Ahmed glaucoma valve (AGV) in refractory glaucoma. PATIENTS AND METHODS: Monocentric, retrospective, comparative clinical trial. Patients suffering from refractory glaucoma after failed surgeries and requiring a further glaucoma procedure including an aqueous shunt were enrolled in this study. The first group AGV included patients with an AGV. The second group eW-B included patients receiving an eyeWatch used in connection with a Baerveldt glaucoma implant. The primary outcome was the success rate, defined as an IOP≤16 mm Hg and reduction of >20% from baseline, and IOP≥5 mm Hg. Secondary outcomes were mean IOP, number of antiglaucoma medications, visual acuity, number and type of complications. RESULTS: Twenty-one patients were included. The mean follow-up time was 13.2±3.4 months. Mean IOP decreased from 24.8±9.0 mm Hg before surgery to 13.8±3.6 mm Hg at 12 months for group AGV, and 27.3±7.0 to 12.8±2.4 mm Hg for group eW-B, respectively (P<0.05). Mean number of glaucoma medications decreased from 3.0±0.7 before surgery to 0.3±0.7 at last control for group AGV, and 2.9±0.8 before surgery to 0.2±0.4 for group eW-B, respectively (P<0.05). The complete and overall success rates were 50% and 58% for group AGV, and 67% and 89% for group eW-B, respectively. CONCLUSIONS: The postoperative adjustability of the eyeWatch is believed to help with getting fewer complications and better IOP management whereas AGV cannot be adjusted postoperatively.

Initial Clinical Results of the eyeWatch: a New Adjustable Glaucoma Drainage Device Used in Refractory Glaucoma Surgery.

PRéCIS:: In this study, we report clinical results after implantation of an adjustable glaucoma drainage device. The intraocular pressure (IOP) profile was efficiently controlled postoperatively as the resistance to aqueous humor outflow was finely adjusted. PURPOSE: The main purpose of this study was to evaluate the safety and efficacy of the new adjustable glaucoma drainage device eyeWatch used in conjunction with a Baerveldt glaucoma implant in refractory glaucoma. PATIENTS AND METHODS: This was a multicentric, prospective, noncomparative clinical trial. Patients older than 18 years of age suffering from refractory glaucoma after failed surgeries, with IOP of ≥20 mm Hg, in whom a further glaucoma procedure using an aqueous shunt was planned, were enrolled in this study. The primary outcome was the success rate, defined as an IOP≤18 mm Hg and reduction of >20% from baseline, IOP≥6 mm Hg. Secondary outcomes were mean IOP, visual acuity, number of antiglaucoma medications, number, and type of complications. RESULTS: Fifteen patients were included. The mean follow-up time was 15.6±3.5 months. The mean baseline IOP decreased from 26.2±6.8 mm Hg before surgery to 11.9±2.8 mm Hg at 12 months (P<0.001). The mean number of glaucoma medications decreased from 3.0±0.7 before surgery to 0.8±0.9 at last visit (P<0.001). The success rate was 40% for complete success and 93% for overall success at last follow-up. Complication rate was 7%. CONCLUSIONS: The novel glaucoma device allows for perioperative and postoperative noninvasive adjustments of the resistance to aqueous humor outflow. This leads to better management of IOP during the early postoperative period, preventing ocular hypotony and eliminating the need for obstructive elements and reinterventions. The rate of complications was low, IOP was adequately controlled and lowered, with a substantial reduction in the number of antiglaucoma medication.

Α systematic review and meta-analysis of the efficacy of aortic anastomotic devices.

OBJECTIVE: One of the factors contributing to complications related to open repair of the aorta is the construction of a hand-sewn anastomosis. Aortic anastomotic devices (AADs), such as the intraluminal ringed graft (IRG), and the anastomotic stenting technique have been developed to perform a sutureless and less complicated anastomosis. This study performed a systematic review and meta-analysis of the literature reporting clinical use of AADs and aimed to assess, primarily, the effect of each device on 30-day overall and operation-related mortality and aortic cross-clamping time and, secondarily, the rate of successful two-sided application of the IRG device and the operation-related morbidity for each device. METHODS: An electronic search was performed using MEDLINE, Scopus, ScienceDirect, and Cochrane Library by two independent authors. Our exclusion criteria included studies incorporating fewer than three patients and studies reporting results solely from animals or in vitro testing, results solely from end-to-side anastomosis, and results solely from endarterectomy procedures. The last search date was February 1, 2018. RESULTS: A total of 41 studies were identified that reported outcomes for the use of three different device types: IRG, anastomotic stenting technique, and surgical staplers. The last two types were classified together as the non-IRG group. The meta-analysis included 27 studies with 50 cohorts incorporating 1260 patients. The median age of the incorporated patients was 61.4 years (range, 51-73 years), and 68.9% were male. The operations were performed for the treatment of acute aortic dissection in 82.3%. The pooled overall 30-day mortality rate varied by device type; IRG devices had a mean rate of all-cause mortality of 9.71%, whereas non-IRG devices were associated with a significantly (I2 = 15.78%; P for Cochrane Q test < .19) lower rate of death (1.47%). The pooled mean aortic cross-clamping time was 35.83 minutes. Metaregression showed that the performance of two-sided anastomosis with the IRG device significantly decreased the aortic cross-clamping time. However, a successful two-sided ringed anastomosis was performed in approximately half of the cases. CONCLUSIONS: Taking into account that the majority of operations were performed for the treatment of acute aortic dissection, AADs had a relatively low rate of 30-day mortality. Despite the observed heterogeneity in study protocols and the small sample size in the non-IRG group, the non-IRG group presented with the lowest 30-day mortality rate. Specific device-related complications between the different device types need further investigation.

Experimental Drainage Device to Reduce Lymphoedema in a Rat Model.

OBJECTIVE: Despite recent advances in pharmacological research and microsurgery, lymphoedema remains an incurable disease that deeply affects quality of life. There is an urgent need for innovative approaches to restore continuous lymph flow in affected tissues. To this end, the efficacy of a subcutaneously implanted draining device in reducing lymphoedema volume in a rat hindlimb lymphoedema model was tested. METHODS: A rat model of chronic lymphoedema was developed by surgical removal of popliteal and inguinal lymph nodes, followed by irradiation. The model was characterised by monitoring limb volume via tape measure, skin water content via dielectric constant measurement, and lymphatic drainage via lymphofluoroscopy. After lymphoedema establishment in 16 Wistar rats, a device made of fenestrated tubing equipped with a miniaturised pumping system, was implanted subcutaneously in the affected limb to restore continuous recirculation of interstitial fluid. RESULTS: Lymphofluoroscopy imaging showed impaired lymphatic drainage following lymphadenectomy and irradiation. Affected limb volume and skin water content increased significantly compared with the untreated limb, with a median (interquartile range) of 3.85 (0.38) cm3 versus 3.03 (0.43) cm3 for volume (n = 16, p = .001) and 26.6 (9.1) versus 16.6 (3.7) cm3 for skin dielectric constant (n = 16, p = .001). Treatment of lymphoedema with the implanted drainage device showed that 5 weeks post-implant excess volume was significantly reduced by 51 ± 18% compared with the pre-implant situation (n = 9 sham group, n = 7 pump group). CONCLUSION: Lymphoedema volume in the rat model was significantly reduced by restoring continuous drainage of excess fluid using a novel subcutaneously implanted device, opening the way to the development of an artificial lymphatic vessel.

Age-related changes in vascular responses to angiotensin-(1-7) in female mice.

The vasodilatory effect of angiotensin-(1-7) seems to vary between sexes, and estradiol (E2) can modulate the magnitude of the Ang-(1-7) vasodilatory response in female rats. However, there are few studies addressing the influence of sex on the age-related vasodilatory effect of Ang-(1-7). Here, we evaluated the vasodilatory response to Ang-(1-7) on vascular ageing. Ang-(1-7) dose-response curves were determined in mice aortic rings from males (old and young) and females (E2 treated/non-treated old and young) mounted in an isolated organ chamber. Abdominal aortic rings were used for protein expression analysis and determination of reactive oxygen species (ROS) and nitric oxide (NO) production. Our results showed that the Ang-(1-7) vasodilatory effect was absent in aorta from old females, contrasting with a full response in vessels from young females. The Ang-(1-7) vasodilatory effect was restored by E2 replacement in old females. A robust increase in Mas receptor, SOD2, NRF-2 and NOX2 expression was observed in aorta from old females, which was normalized by E2. This effect of E2 was also associated with lower production of ROS and normal levels of NO. In conclusion, our data demonstrated that pathways involved in the Ang-(1-7) vasodilatory response in female mice is affected by hormonal changes in ageing and rescued by E2.

Apelin-13 treatment enhances the stability of atherosclerotic plaques.

BACKGROUND: Apelin is an endogenous peptidergic system which modulates cardiovascular function. Recent studies pointed out a fundamental contribution of apelin on atherosclerosis development; however, such reports revealed contradictory data, and to date, it is difficult to accurately define a beneficial or deleterious role. To better understand apelin function on atherosclerosis, we aimed to investigate apelin-13 treatment effects on atherosclerotic plaques composition. DESIGN: Apolipoprotein E gene-deleted mice were fed on Western-type diet for 11 weeks. Atherosclerotic plaque formation was induced in the carotid artery by a shear stress modifier device, which exposes the same vessel to distinct patterns of shear stress enabling the formation of plaques with different composition. Mice were treated with apelin-13 (2 mg kg-1 day-1 ) or vehicle for the last 3 weeks. RESULTS: Apelin-13 treatment did not alter the lipid content of low shear stress- and oscillatory shear stress-induced plaques in the carotid. However, apelin-13 greatly ameliorated plaque stability by increasing intraplaque collagen content and reducing MMP-9 expression. Furthermore, apelin-13 decreased the infiltration of inflammatory cells (neutrophil and macrophage) and intraplaque reactive oxygen species content. Interestingly, apelin-13 treatment reduced total cholesterol, LDL levels and free fatty acid serum levels, while HDL, triglycerides serum levels were not significantly changed. CONCLUSIONS: Apelin-13 treatment for 3 weeks did not alter the lesion size, but it significantly enhanced the stable phenotype of atherosclerotic plaques and improved serum lipid profile. These results indicate that activation of apelin system decreases plaque vulnerability.

Varicocele percutaneous embolization outcomes in a pediatric group: 7-year retrospective study.

PURPOSE: Percutaneous embolization and surgical repair are the current treatment options for varicocele, but determining method superiority remains controversial. In this retrospective study, we evaluate the technical success, complication and recurrence rates following percutaneous embolization in a pediatric group, which were compared to reported outcomes for surgical repairs. METHODS: Thirty children treated for percutaneous varicocele embolization were recruited. The side and grade of varicocele, symptoms, testicular asymmetry, mean recurrence time, total radiation dose and complications were evaluated. Recurrence and follow-up complications due to embolization were also reviewed. RESULTS: The venography showed retrograde filling of the internal spermatic vein with the identification of aberrantly fed vessels in 23 % of patients. None of the patients suffered from procedure complications except one who had venous injury which was treated with a sclerosing agent. The technical success rate was 93 % (28 patients) with a recurrence rate of 13 % (4 patients). Interestingly, the mean radiation dose used was 862.5 µGy m(2), 3 times lower than abdominal CT. CONCLUSION: Considering the intravascular nature of embolization, which aims to avoid testicular artery and spermatic cord damage (difficult to avoid with the surgical method), and consequently a lower complication rate, along with the same success rate and recurrence rate, our study supports that embolization is a superior method to surgical interventions.

Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice.

Angiotensin (Ang) II contributes to the development of atherosclerosis, while Ang-(1-7) has atheroprotective actions. Accordingly, angiotensin-converting enzyme 2 (ACE2), which breaks-down Ang II and forms Ang-(1-7), has been suggested as a target against atherosclerosis. Here we investigated the actions of diminazene, a recently developed ACE2 activator compound, in a model of vulnerable atherosclerotic plaque. Atherosclerotic plaque formation was induced in the carotid artery of ApoE-deficient mice by a shear stress (SS) modifier device. The animals were treated with diminazene (15mg/kg/day) or vehicle. ACE2 was strongly expressed in the aortic root and low SS-induced carotid plaques, but poorly expressed in the oscillatory SS-induced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorated the composition of aortic root and low SS-induced carotid plaques by increasing collagen content and decreasing both MMP-9 expression and macrophage infiltration. Interestingly, these beneficial effects were not observed in the oscillatory SS-induced plaque. Additionally, diminazene treatment decreased intraplaque ICAM-1 and VCAM-1 expression, circulating cytokine and chemokine levels and serum triglycerides. In summary, ACE2 was distinctively expressed in atherosclerotic plaques, which depends on the local pattern of shear stress. Moreover, diminazene treatment enhances the stability of atherosclerotic plaques.

Treatment with sulphated galactan inhibits macrophage chemotaxis and reduces intraplaque macrophage content in atherosclerotic mice.

Experimental data from animal models and clinical studies support connections between the haemostasis and inflammation in atherogenesis. These interfaces among inflammation and thrombogenesis have been suggested as targets for pharmacological intervention to reduce disease progression. We hypothesize that the recently discovered antithrombotic drug Sulphated Galactan (SG) (isolated from the red marine alga Acanthophora muscoides) might reduce atherosclerotic plaque vulnerability and inflammatory gene expression in 10-week aged apolipoprotein E deficient (ApoE-/-) mice under high-cholesterol diet for additional 11weeks. Then, the underlying cellular mechanisms were investigated in vitro. SG (10mg/kg) or Vehicle was subcutaneously injected from week 6 until week 11 of the diet. Treatment with SG reduced intraplaque macrophage and Tissue Factor (TF) content as compared to Vehicle-treated animals. Intraplaque TF co-localized and positively correlated with macrophage rich-areas. No changes on atherosclerotic plaque size, and other intraplaque features of vulnerability (such as lipid, neutrophil, MMP-9 and collagen contents) were observed. Moreover, mRNA expression of MMPs, chemokines and genetic markers of Th1/2/reg/17 lymphocyte polarization within mouse aortic arches and spleens was not affected by SG treatment. In vitro, treatment with SG dose-dependently reduced macrophage chemotaxis without affecting TF production. Overall, the chronic SG treatment was well tolerated. In conclusion, our results indicate that SG treatment reduced intraplaque macrophage content (by impacting on cell recruitment) and, concomitantly, intraplaque TF content of potential macrophage origin in atherosclerotic mice.

Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice.

Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.

Role of the renin-angiotensin system on abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex degenerative disease, which leads to morbidity and mortality in a large portion of the elderly population. Current treatment options for AAA are quite limited as there is no proven indication for pharmacological therapy and surgery is recommended for AAA larger than 5·5 cm in luminal diameter. Thus, there is a great need to elucidate the underlying pathophysiological cellular and molecular mechanisms to develop effective therapies. In this narrative review, we will discuss recent findings concerning some potential molecular and clinical aspects of the renin-angiotensin system (RAS) in AAA pathophysiology. MATERIALS AND METHODS: This narrative review is based on the material found on MEDLINE and PubMed up to April 2013. We looked for the terms 'angiotensin, AT1 receptor, ACE inhibitors' in combination with 'abdominal aortic aneurysm, pathophysiology, pathways'. RESULTS: Several basic research and clinical studies have recently investigated the role of the RAS in AAA. In particular, the subcutaneous infusion of Angiotensin II has been shown to induce AAA in Apo56 knockout mice. On the other hand, the pharmacological treatments targeting this system have been shown as beneficial in AAA patients. CONCLUSIONS: Emerging evidence suggests that RAS may act as a molecular and therapeutic target for treating AAA. However, several issues on the role of RAS and the protective activities of angiotensin-converting enzyme (ACE) inhibitors and Angiotensin 1 receptors blockers against AAA require further clarifications.

An oral formulation of angiotensin-(1-7) reverses corpus cavernosum damages induced by hypercholesterolemia.

INTRODUCTION: The renin angiotensin system plays a crucial role in erectile function. It has been shown that elevated angiotensin-II levels contribute to the development of erectile dysfunction (ED). Oppositely, angiotensin-(1-7) (Ang-[1-7]) mediates penile erection by activation of receptor Mas. Recently, we have developed a formulation based on Ang-(1-7) inclusion in cyclodextrin (CyD) [Ang-(1-7)-CyD], which allows for the oral administration of Ang-(1-7). AIM: In the present study, we evaluated the effects of chronic treatment with Ang-(1-7)-CyD on penile fibrosis, oxidative stress, and endothelial function in hypercholesterolemic mice. METHODS: Apolipoprotein(Apo)E-/- mice fed a Western-type diet for 11 weeks received Ang-(1-7)-CyD or vehicle during the final 3 weeks. Collagen content and reactive oxygen species (ROS) production within the corpus cavernosum were evaluated by Sirius red and dihydroethidium staining, respectively. Protein expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate (NADPH) subunits (p67-phox and p22-phox), and AT1 and Mas receptors in the penis was assessed by Western blotting. Nitric oxide (NO) production was measured by Griess assay in the mice serum. Cavernosal strips were mounted in an isometric organ bath to evaluate the endothelial function. MAIN OUTCOME MEASURES: The effect of Ang-(1-7)-CyD treatment on penile fibrosis, oxidative stress, and endothelial function in hypercholesterolemia-induced ED. RESULTS: Ang-(1-7)-CyD treatment reduced collagen content in the corpus cavernosum of ApoE-/- mice. This effect was associated with an attenuation of ROS production and a diminished expression of NADPH. Furthermore, Ang-(1-7)-CyD treatment augmented the expression of nNOS and eNOS in the penis and elevated vascular NO production. Importantly, these effects were accompanied by an improvement in cavernosal endothelial function. CONCLUSION: Long-term treatment with Ang-(1-7)-CyD reduces penile fibrosis associated with attenuation of oxidative stress. Additionally, cavernosal endothelial function in hypercholesterolemic mice was markedly improved. These results suggest that Ang-(1-7)-CyD might have significant therapeutic benefits for the treatment of erectile dysfunction.

Treatment with Evasin-3 reduces atherosclerotic vulnerability for ischemic stroke, but not brain injury in mice.

Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a 'cast' carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes.

The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis: a potential target for treating thrombotic diseases.

Despite many therapeutic advances leading to increasingly effective drug treatments, thrombotic events (such as ischaemic stroke, pulmonary embolism, deep venous thrombosis and acute myocardial infarction) still represent a major worldwide cause of morbidity and mortality. Remarkable effort has been made to identify new drug targets. There is growing evidence indicating that the recently described counter-regulator axis of the renin-angiotensin system (RAS), composed of Angiotensin-Converting Enzyme 2 (ACE2), Angiotensin-(1-7) and the Mas receptor, has protective effects against thrombosis. In addition, it could be considered as a promising target for treating or preventing this disease. In this narrative review, we focused on the recent findings of the role of the ACE2/Angiotensin-(1-7)/Mas axis on the haemostatic process and its therapeutic potential.

3D simulation of the aqueous flow in the human eye.

Glaucoma results in an increase in the resistance of the aqueous humor outflow, which in turn leads to an increase of the intraocular pressure (IOP). Several treatments are proposed to reduce and stabilize the IOP that include medications, filtering surgery and glaucoma drainage devices (GDD). So far computational fluid dynamics (CFD) modeling of the eye drainage system has not yet been well studied. Therefore our goal was to provide a 3D CFD model of the eye based on the anatomy of a real human eye. Such a tool would serve for future evaluation of new glaucoma surgical techniques involving, for example, GDD. The model was based on stacks of microphotographs from human eye slides from which digital processing of the images of the eye structure and 3D reconstruction of the model were performed. Simulations of the distribution of pressure and flow velocity in the model of a healthy eye gave results comparable to physiology references. Mimicking glaucoma conditions led to an increase of the IOP from normal range, which went down to lower values after a filtering procedure. Further refinements in the boundary conditions for the filtering procedure shall improve the accuracy of this innovative tool for modeling glaucoma surgery.

Effects of an aging vascular model on healthy and diseased hearts.

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.