Morphological and physiological changes in the vasculature have been described in the evolution and maintenance of hypertension. Hypertension-induced vascular dysfunction may present itself as a contributing, or consequential factor, to vascular remodeling caused by chronically elevated systemic arterial blood pressure. Changes in all vessel layers, from the endothelium to the perivascular adipose tissue (PVAT), have been described. This mini-review focuses on the current knowledge of the structure and function of the vessel layers, specifically muscular arteries: intima, media, adventitia, PVAT, and the cell types harbored within each vessel layer. The contributions of each cell type to vessel homeostasis and pathophysiological development of hypertension will be highlighted.
The depressive phenotype in this BCG model of chronic inflammation is sensitive to antidepressants and consistent with clinical reports showing that paroxetine pretreatment prior to immunotherapy can prevent the development of psychiatric symptoms.
Diabetic bladder dysfunction (DBD) affects up to 50% of all patients with diabetes, characterized by symptoms of both overactive and underactive bladder. Although most diabetic bladder dysfunction studies have been performed using models with type 1 diabetes, few have been performed in models of type 2 diabetes, which accounts for ~90% of all diabetic cases. In a type 2 rat model using a high-fat diet (HFD) and two low doses of streptozotocin (STZ), we examined voiding measurements and functional experiments in urothelium-denuded bladder strips to establish a timeline of disease progression. We hypothesized that overactive bladder symptoms (compensated state) would develop and progress into symptoms characterized by underactive bladder (decompensated state). Our results indicated that this model developed the compensated state at 1 wk after STZ and the decompensated state at 4 mo after STZ administration. Diabetic bladders were hypertrophied compared with control bladders. Increased volume per void and detrusor muscle contractility to exogenous addition of carbachol and ATP confirmed the development of the compensated state. This enhanced contractility to carbachol was not due to increased levels of M3 receptor expression. Decompensation was characterized by increased volume per void, number of voids, and contractility to ATP but not carbachol. Thus, progression from the compensated to decompensated state may involve decreased contractility to muscarinic stimulation. These data suggest that the compensated state of DBD progresses temporally into the decompensated state in the male HFD/STZ model of diabetes; therefore, this male HFD/STZ model can be used to study the progression of DBD.
The accumulation of misfolded‐aggregated proteins is linked to an increasing number of degenerative diseases, including hypertension. Although protein damage and misfolding are an inevitable consequence of normal cellular function, multiple proteostasis mechanisms are devoted to the repair or clearance of damaged proteins in order to prevent proteotoxicity. Autophagy is the constitutive and basally active recycling mechanism responsible for protein quality control. Previously, our data has suggested decreased autophagy in conduit and resistance arteries from spontaneously hypertensive rats (SHR); however, direct measurement of autophagic activity, as well as the proteotoxic consequences of undegraded, misfolded protein has not been performed. Furthermore, the effects of reconstituting autophagic activity on vascular reactivity are currently unknown. We hypothesized that mesenteric resistance arteries (MRA) from adult (14 weeks old) SHR would have decreased autophagic activity in lysosomes extracted from arteries and this would be associated with increased misfolded protein oligomers. Therefore, we further hypothesized that upregulation of autophagy via mammalian target of rapamycin (mTOR) inhibition would decrease contraction and improve relaxation in isolated MRA from SHR mounted on wire myographs. We observed that the activity of acid phosphatase, the major acid hydrolase in lysosomes, from arterial lysosomes (pooled mesenteric arteries and aorta) was decreased in SHR (μmol/min, Wistar: 0.51±0.06 vs. SHR: 0.24±0.02, p<0.05). This diminished arterial autophagic activity was observed in conjunction with the increased presence of insoluble protein deposition. Specifically, SHR MRA contained increased fibrillar amyloid oligomers, especially along the endothelium monolayer, as indicated by Congo red staining (Figure 1). When autophagy was reconstituted in isolated MRA via mTOR inhibition with Everolimus (EV; first generation mTOR inhibitor) for 1 hr, we observed that the maximum contraction to phenylephrine was reduced [Emax (mN), Vehicle: 19.8±0.5 vs. EV (0.1 nM): 10.7±0.5 vs. EV (0.1 μM): 8.5±1.0, p<0.05] and the contraction to high concentrations acetylcholine was prevented [LogEC50, Vehicle: −6.9±0.1 vs. EV (0.1 nM): −9.2±0.4 vs. EV (0.1 μM): −8.2±0.1, p<0.05]. Overall, these data reveal that SHR have impaired arterial lysosomal activity and this is associated with the accumulation of misfolded proteins. As a result, reconstituting arterial autophagic activity improved vascular function and could be a novel therapeutic treatment for proteotoxicity in hypertension.
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NIH (K99GM118885 and P01HL134604).
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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