Adhesion of monocytes to the vascular endothelium frequently leads to an inflammatory response, which contributes to hypertension and vascular remodeling. Vascular cellular adhesion molecule-1 (VCAM-1) plays an important role in leukocyte adhesion and migration during inflammatory diseases. However, its role in angiotensin (Ang) II -induced hypertension and vascular dysfunction remains largely unknown. Wild-type (WT) mice were administered a VCAM-1 neutralizing antibody (0.1 or 0.2 mg/mouse/day) or IgG control and then infused with Ang II (490 ng kg−1 min−1) or saline continuously for 14 days. Systolic blood pressure (SBP) was measured with a tail-cuff system, pathological changes in the aorta were assessed by histological staining, and vascular relaxation was analyzed an aortic ring assay. Our results indicated that compared with saline infusion, Ang II infusion significantly upregulated VCAM-1 expression in the mouse aorta and serum. Moreover, Ang II infusion markedly increased arterial hypertension, wall thickness, fibrosis, infiltration of Mac-2+ macrophages, reactive oxygen species (ROS) production and vascular relaxation dysfunction. Conversely, blockade of VCAM-1 with a neutralizing antibody substantially alleviated these effects. In vitro experiments further confirmed that the VCAM-1 neutralizing antibody inhibited Ang II-induced macrophage adhesion and migration and DNA damage and oxidative stress in endothelial cells (ECs). In conclusion, these results indicate that blockade of VCAM-1 exerts a protective effect against Ang II-induced arterial hypertension and dysfunction by regulating monocytes adhesion and infiltration into the endothelium and represents a novel therapeutic approach for hypertension.

Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/−) and wild-type (VEGFR-3f/f) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.

Aim Insulin resistance is a feature of type 2 diabetes mellitus (T2DM). The estimated glucose disposal rate (eGDR), a validated marker for insulin resistance, is associated with complications of diabetes, but few studies have explored the relationship between eGDR and renal outcomes in T2DM. This study investigated the value of eGDR in predicting renal progression in T2DM. Methods A total of 956 T2DM patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2and a 5-year follow-up were enrolled. Primary outcomes were rapid eGFR decline, eGFR <60 mL/min/1.73m2, and composite renal endpoint consisting of 50% eGFR decline, doubling of serum creatinine, or end-stage renal disease. A continuous scale with restricted cubic spline curves and a generalized linear model were applied to evaluate the associations between eGDR and primary outcomes. Results 23.95% of patients experienced rapid eGFR decline, 21.97% with eGFR <60 mL/min/1.73m2, and 12.13% with the composite renal endpoint. eGDR showed a relationship with follow-up eGFR and percent change in eGFR (P<0.001). eGDR <6.34 mg/kg/min was an independent risk factor for rapid eGFR decline, eGFR<60 mL/min/1.73m2or the composite renal endpoint(P<0.05). Compared with eGDR of 5.65∼6.91 mg/kg/min, eGDR levels >8.33 mg/kg/min decreased the risk of rapid eGFR decline by 75%, eGFR<60 mL/min/1.73m2 by 60%, and the composite renal endpoint by 61%. Subgroup analysis was performed by sex, age, and diabetes duration, which showed that eGDR was associated with primary outcomes. Conclusions Lower eGDR is a predictive factor for renal deterioration in T2DM patients.