Pharmacological Blockade of NLRP3 Inflammasome/IL-1ß-Positive Loop Mitigates Endothelial Cell Senescence and Dysfunction.

The clinical relevance of IL-1ß in chronic inflammation underlying atherosclerosis has been reinforced by recent evidence associating pharmacological inhibition of the cytokine with lower cardiovascular risk. Previously, we have demonstrated a direct involvement of IL-1ß in endothelial senescence. Therefore, this can be a key mechanism contributing to the sterile inflammatory milieu associated with aging, termed inflammaging. In the present study, we have evaluated whether a positive feedback of IL-1ß in the NLRP3 inflammasome via NF-κB could promote human endothelial senescence in vitro and murine endothelial dysfunction in vivo. Our results indicate that the NLRP3 inflammasome is pivotal in mediating the detrimental effects of IL-1ß, showing that auto-activation is a crucial feature boosting endothelial cell senescence in vitro, which is paralleled by vascular dysfunction in vivo. Hence, the inhibitor of NLRP3 inflammasome assembly, MCC 950, was able to disrupt the aforementioned positive loop, thus alleviating inflammation, cell senescence and vascular dysfunction. Besides, we explored alternative NLRP3 inflammasome inhibitory agents such as the RAS heptapeptide Ang-(1-7) and the anti-aging protein klotho, both of which demonstrated protective effects in vitro and in vivo. Altogether, our results highlight a fundamental role for the hereby described NLRP3 inflammasome/IL-1ß positive feedback loop in stress-induced inflammaging and the associated vascular dysfunction, additionally providing evidence of a potential therapeutic use of MCC 950, Ang-(1-7) and recombinant klotho to block this loop and its deleterious effects.

Endothelial C-type natriuretic peptide maintains vascular homeostasis.

The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor-C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.

Characterization of endothelium-dependent relaxations in the mesenteric vasculature: a comparative study with potential pathophysiological relevance.

BACKGROUND: Endothelium-dependent relaxations in human adult mesenteric microvessels involve 3 different main mechanisms: cyclooxygenase (COX)-derived prostanoids, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF), which elicits vascular smooth muscle hyperpolarization and relaxation. There are some pathological conditions with an abnormal balance between mesenteric vasoconstriction and vasodilatation inputs leading to endothelial dysfunction and tissue injury. PURPOSE: The purpose was to characterize the mechanisms mediating endothelium-dependent relaxation and differences in children and adult mesenteric microvessels. METHODS: Microvessels were dissected from omentum obtained from children (3-6 years old) and adults (25-41 years old) and mounted as ring preparations in a small vessel myograph. RESULTS: In microvessels precontracted with a thromboxane analogue, the endothelium-dependent relaxations to bradykinin (10 nmol/L to 30 µmol/L) mediated by EDHF, that is, nonsensitive to COX (10 µmol/L indomethacin) and NO synthase blockade (100 µmol/L N-nitro-L-arginine methyl ester), were higher in children than in adults. When EDHF was blunted by a depolarizing precontraction with KCl, the remaining COX- and NO-dependent relaxations were significantly lower in children. CONCLUSIONS: The EDHF's role in the endothelium-dependent relaxations is higher in children's vasculature. This suggests that endothelial dysfunction in mesenteric microvessels in children is likely more dependent on EDHF-related mechanisms rather than on NO- or COX-derived prostanoids.

Endoscopic treatment of vesicoureteral reflux in a paediatric surgery ambulatory unit.

BACKGROUND: Vesicoureteral reflux (VUR) is a major urological problem in children. Its incidence ranges from 1 to 3% in healthy children. MATERIALS AND METHODS: We treated 38 children and analysed their data on age, sex, reflux grade, laterality, and results of endoscopic treatment (ET), at the different grades of reflux. All children were operated on an Ambulatory Surgery basis, studying the complications and post-operative course. RESULTS: Thirty-eight patients were operated during a period of six years, of age between one and twelve years. VUR was bilateral in 24 (63%) patients, unilateral in 14 (34%), with a collection of a total of 62 renal units or ureters. In 29 children (76%), 46 refluxing ureters (70%) completely disappeared after just 1 ET. Nine patients (24%) with 16 ureteral units (30%) received a second ET, with the reflux disappearing successfully in seven children (12 ureteral units), changing the success rate in the disappearance of VUR, after two injections of Deflux, to 90% of the total group of ureters (58 of 62). CONCLUSION: The endoscopic treatment of VUR has become the first choice of treatment to control the primary reflux, not just because of the good results, but because of the low post-operative morbidity and the direct relationship with the Ambulatory Surgery Unit.