Abstract 34: Diminished Contractile Capability In Cerebral Vascular Smooth Muscle Cells In The TgF344-AD Rat Model Of Alzheimer's Disease

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Xing Fang ◽  
Huawei Zhang ◽  
Yedan Liu ◽  
Shaoxun Wang ◽  
Baoying Zheng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Rat Model ◽  
Perfusion Pressure ◽  
Vascular Dysfunction ◽  
Muscle Cells ◽  
Model Of Alzheimer’S Disease ◽  
Cerebral Vascular

We recently reported that cerebral vascular dysfunction leads to impaired autoregulation of cerebral blood flow (CBF), neurovascular coupling (NVC), and blood-brain barrier (BBB) leakage. The present study examined if cerebral vascular dysfunction precedes cognitive impairment in the TgF344-AD (AD) rat model of Alzheimer's disease. In the present study, we confirmed that the AD rats develop learning and memory deficits beginning at 24-week of age using an eight-arm water maze. AD rats (n = 11) took a longer time to escape and displayed more errors than age-matched wildtype (WT) rats (n = 6). We also completed a longitudinal comparison of the myogenic response (MR) of the middle cerebral artery (MCA) and found that the MR was similar in AD and WT rats at 8- to 12-week of age when perfusion pressure was increased from 40 to 180 mmHg. However, the MR was significantly reduced in 16-week old AD rats (n = 6) as the inner diameter of the MCA only decreased by 8.2 ± 2.4% when perfusion pressure was increased from 40 to 180 mmHg compared with 14.5% ± 2.0% in age-matched WT rats (n = 6). The impaired MR of the MCA was exacerbated in AD rats with aging. Autoregulation of CBF AD rats (n = 4) in vivo was impaired in the surface and deep cortex at 24-week of age compared to age-matched WT rats (n = 4). Furthermore, we found the contractile capability of the cerebral vascular smooth muscle cells (VSMCs) isolated from AD rats (n = 4) was significantly reduced compared with WT rats (n = 4), detected by the reduction in size of 15.7 ± 0.9% vs. 25.4 ± 1.0% using a collagen gel-based assay kit. These results provide evidence that cerebral VSMC dysfunction, impaired MR, and autoregulation of CBF precede the development of memory and learning deficits in the TgF344-AD rat model. However, the underlying mechanisms for the loss of VSMCs contractility in this AD model overexpressing mutant human amyloid precursor protein ( APPsw ) and presenilin 1 ( PS1ΔE9 ) genes remain to be determined. Nevertheless, these results provide novel insight into the vascular contribution to AD.

scholarly journals Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model

2016 ◽  
pp. gfw274 ◽  
Author(s):  
Stacey Dineen Rodenbeck ◽  
Chad A. Zarse ◽  
Mikaela L. McKenney-Drake ◽  
Rebecca S. Bruning ◽  
Michael Sturek ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Smooth Muscle ◽  
Kidney Disease ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Intracellular Calcium ◽  
Vascular Smooth Muscle Cells ◽  
Rat Model ◽  
Muscle Cells

Abstract 209: Resistin Regulates Dynamin-Related Protein 1, a Mitochondrial Fission Protein in Vascular Smooth Muscle Cells

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Takara A Scott ◽  
Sharon Francis
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Dysfunction ◽  
Mitochondrial Fission ◽  
Muscle Cells ◽  
Related Protein ◽  
Mitochondrial Fragmentation ◽  
Over Expression

Recent studies indicate increased mitochondrial fission and organ dysfunction in models of obesity. While the mechanisms for this morphological alteration are not completely understood it is likely that the altered adipokine profile that occurs during obesity may play a permissive role in enhanced mitochondrial fragmentation. In this study, we investigated the role of resistin, a pro-inflammatory adipokine that is elevated in the plasma of obese individuals, on regulation of the mitochondrial fission protein, dynamin-related protein 1(DNM1L) in vascular smooth muscle cells (VSMCs). We hypothesized that serum and glucocorticoid inducible kinase 1 (SGK1) plays a role in resistin-induced mitochondrial fission expression in VSMCs. In dose and time response studies, we found that resistin stimulated DNM1L protein levels in both rat and human aortic smooth muscle cells suggesting a role for resistin in regulation of mitochondrial fission. In addition, we observed that resistin enhances expression and activity of SGK1. To determine whether SGK1 regulates resistin-mediated expression of DNM1L, we examined the effect of SGK1 over-expression, or inhibition on resistin-induced expression of DNM1L. Over-expression of wildtype SGK1 potentiated resistin-mediated DNM1L expression, while dominant-negative SGK1 inhibited resistin-mediated expression of DNM1L in human VSMC. In conclusion, we have demonstrated for the first time that SGK1 is a potential downstream mediator of resistin. Interestingly, SGK1 activity has been linked to pathological vascular remodeling in various cardiovascular disease settings. Our data suggests that the elevated plasma levels of resistin that occur in obese individuals may lead to activation of SGK1. This in turn, could exacerbate mitochondrial fragmentation in VSMC and predispose to the development of vascular dysfunction that is evident during obesity. Together with further mitochondrial fission studies, additional elucidation of how resistin also alters components of mitochondrial fusion machinery may uncover novel mechanisms of potential theraputic targets for obesity-mediated vascular dysfunction.

scholarly journals 181 Nox compartmentalization and protein oxidation in vascular smooth muscle cells – implications in vascular dysfunction in hypertension

Heart ◽  
2017 ◽  
Vol 103 (Suppl 5) ◽  
pp. A125.1-A125
Author(s):  
Livia de Lucca Camargo ◽  
Augusto Cesar Montezano ◽  
Sofia Tsiropoulou ◽  
Adam Harvey ◽  
Katie Hood ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Protein Oxidation ◽  
Vascular Dysfunction ◽  
Muscle Cells

scholarly journals Differential effects of superoxide and hydrogen peroxide on myogenic signaling, membrane potential, and contractions of mouse renal afferent arterioles

2016 ◽  
Vol 310 (11) ◽  
pp. F1197-F1205 ◽  
Author(s):  
Lingli Li ◽  
En Yin Lai ◽  
Anton Wellstein ◽  
William J. Welch ◽  
Christopher S. Wilcox
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Perfusion Pressure ◽  
Principal Component ◽  
Muscle Cells ◽  
Luminal Diameter ◽  
Afferent Arterioles

Myogenic contraction is the principal component of renal autoregulation that protects the kidney from hypertensive barotrauma. Contractions are initiated by a rise in perfusion pressure that signals a reduction in membrane potential ( Em) of vascular smooth muscle cells to activate voltage-operated Ca2+ channels. Since ROS have variable effects on myogenic tone, we investigated the hypothesis that superoxide (O2·−) and H2O2 differentially impact myogenic contractions. The myogenic contractions of mouse isolated and perfused single afferent arterioles were assessed from changes in luminal diameter with increasing perfusion pressure (40–80 mmHg). O2·−, H2O2, and Em were assessed by fluorescence microscopy during incubation with paraquat to increase O2·− or with H2O2. Paraquat enhanced O2·− generation and myogenic contractions (−42 ± 4% vs. −19 ± 4%, P < 0.005) that were blocked by SOD but not by catalase and signaled via PKC. In contrast, H2O2 inhibited the effects of paraquat and reduced myogenic contractions (−10 ± 1% vs. −19 ± 2%, P < 0.005) and signaled via PKG. O2·− activated Ca2+-activated Cl− channels that reduced Em, whereas H2O2 activated Ca2+-activated and voltage-gated K+ channels that increased Em. Blockade of voltage-operated Ca2+ channels prevented the enhanced myogenic contractions with paraquat without preventing the reduction in Em. Myogenic contractions were independent of the endothelium and largely independent of nitric oxide. We conclude that O2·− and H2O2 activate different signaling pathways in vascular smooth muscle cells linked to discreet membrane channels with opposite effects on Em and voltage-operated Ca2+ channels and therefore have opposite effects on myogenic contractions.

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