Mechanotransduction and the Myogenic Response in Diabetes

We have reported that the myogenic response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded Hypertensive (FHH) rats. Transfer of a region of chromosome 1 containing γ-adducin (Add3) from the Brown Norway rat rescued the vascular dysfunction and the development of renal disease. To examine whether Add3 is a viable candidate gene altering renal and cerebral hemodynamics in FHH rats, we knocked down the expression of Add3 in rat Af-arts and MCAs cultured for 36-h using a 27-mer Dicer-substrate short interfering RNA (DsiRNA). Control Af-arts constricted by 10 ± 1% in response to an elevation in pressure from 60 to 120 mmHg but dilated by 4 ± 3% when treated with Add3 DsiRNA. Add3 DsiRNA had no effect on the vasoconstrictor response of the Af-art to norepinephrine (10−7 M). Add3 DsiRNA had a similar effect on the attenuation of the myogenic response in the MCA. Peak potassium currents were threefold higher in smooth muscle cells isolated from Af-arts or MCAs transfected with Add3 DsiRNA than in nontransfected cells isolated from the same vessels. This is the first study demonstrating that Add3 plays a role in the regulation of potassium channel function and vascular reactivity. It supports the hypothesis that sequence variants in Add3, which we previously identified in FHH rats, may play a causal role in the impaired myogenic response and autoregulation in the renal and cerebral circulation.

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Myogenesis in paraxial mesoderm: preferential induction by dorsal neural tube and by cells expressing Wnt-1

Development ◽

10.1242/dev.121.11.3675 ◽

1995 ◽

Vol 121 (11) ◽

pp. 3675-3686 ◽

Cited By ~ 40

Author(s):

H.M. Stern ◽

A.M. Brown ◽

S.D. Hauschka

Keyword(s):

Neural Tube ◽

Muscle Development ◽

Paraxial Mesoderm ◽

Myogenic Response ◽

Dorsal Neural Tube ◽

Ventral Neural Tube ◽

Myogenic Induction ◽

Inductive Activity

Previous studies have demonstrated that the neural tube/notochord complex is required for skeletal muscle development within somites. In order to explore the localization of myogenic inducing signals within the neural tube, dorsal or ventral neural tube halves were cultured in contact with single somites or pieces of segmental plate mesoderm. Somites and segmental plates cultured with the dorsal half of the neural tube exhibited 70% and 85% myogenic response rates, as determined by immunostaining for myosin heavy chain. This response was slightly lower than the 100% response to whole neural tube/notochord, but was much greater than the 30% and 10% myogenic response to ventral neural tube with and without notochord. These results demonstrate that the dorsal neural tube emits a potent myogenic inducing signal which accounts for most of the inductive activity of whole neural tube/notochord. However, a role for ventral neural tube/notochord in somite myogenic induction was clearly evident from the larger number of myogenic cells induced when both dorsal neural tube and ventral neural tube/notochord were present. To address the role of a specific dorsal neural tube factor in somite myogenic induction, we tested the ability of Wnt-1-expressing fibroblasts to promote paraxial mesoderm myogenesis in vitro. We found that cells expressing Wnt-1 induced a small number of somite and segmental plate cells to undergo myogenesis. This finding is consistent with the localized dorsal neural tube inductive activity described above, but since the ventral neural tube/notochord also possesses myogenic inductive capacity yet does not express Wnt-1, additional inductive factors are likely involved.

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Coronary artery myogenic response in a genetic model of hypertrophic cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00606.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. H2244-H2249 ◽

Cited By ~ 10

Author(s):

Henrik H. Petersen ◽

Jonathan Choy ◽

Brian Stauffer ◽

Farzad Moien-Afshari ◽

Christian Aalkjaer ◽

...

Keyword(s):

Transgenic Mouse ◽

Genetic Model ◽

Morphological Characteristics ◽

Myogenic Tone ◽

Chain Gene ◽

Myogenic Response ◽

Cardiac Phenotype ◽

First Time ◽

Pressure Myograph ◽

Intravascular Pressure

Hypertrophic cardiac myopathy (HCM) is the leading cause of mortality in young athletes. Abnormalities in small intramural coronary arteries have been observed at autopsy in such subjects. The walls of these intramural vessels, especially in the ventricular septum, are thickened, and the lumen frequently appears narrowed. Whether these morphological characteristics have functional correlates is unknown. We studied coronary myogenic tone in a transgenic mouse model of HCM that has mutations in the cardiac α-myosin heavy chain gene. This transgenic mouse has a cardiac phenotype that resembles that occurring in humans. We examined the possible vascular contributions to the pathology of HCM. Septal arteries from 3- and 11-mo-old wild-type (WT) and transgenic (TG) mice were studied on a pressure myograph. The myogenic response to increased intravascular pressure in older animals was significantly reduced [maximal constriction: 32 ± 4% (TG) and 46 ± 4% (WT), P < 0.05]. After inhibition of endothelin receptors with bosentan, both WT and TG mice had similar increases in myogenic constriction. The sensitivity to exogenous endothelin was significantly reduced in TG mice, suggesting that the reduced myogenic constriction in HCM was due to reduced receptor sensitivity. In conclusion, we show for the first time that 1) myogenic tone in the coronary septal artery of the mouse is regulated by a basal release of endothelin, and 2) pressure-induced myogenic activation is attenuated in HCM, possibly consequent to a reduction in endothelin responsiveness. The associated reduction in coronary vasodilatory reserve may increase susceptibility to ischemia and arrhythmias.

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Mechanism of enhanced myogenic response in arterioles during sympathetic nerve stimulation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.263.4.h1185 ◽

1992 ◽

Vol 263 (4) ◽

pp. H1185-H1189 ◽

Cited By ~ 13

Author(s):

P. Ping ◽

P. C. Johnson

Keyword(s):

Nerve Stimulation ◽

Sympathetic Nerve ◽

Similar Degree ◽

Sartorius Muscle ◽

Myogenic Response ◽

Pressure Reduction ◽

Sympathetic Nerve Stimulation ◽

Norepinephrine Infusion ◽

Cell Velocity ◽

Significant Mechanism

In a previous study we found that the arteriolar myogenic response was enhanced during sympathetic nerve stimulation in the cat sartorius muscle. In this study we determined whether the enhancement was unique to sympathetic nerve stimulation. Changes of arteriolar diameter and red cell velocity during femoral arterial pressure reduction from 110 to 60 mmHg were examined. Arterioles of 40 microns diameter were constricted by norepinephrine infusion to a similar degree as sympathetic nerve stimulation. Arteriolar dilation to pressure reduction was significantly enhanced during norepinephrine infusion and was not significantly different from that during sympathetic nerve stimulation. This indicates that junctional release of transmitters is not essential and rules out prejunctional inhibition of neurotransmitter release during pressure reduction as a significant mechanism in the enhanced dilation. Arteriolar dilation to pressure reduction was also enhanced during vasopressin or BAY K 8644 (a calcium channel agonist) infusion. In all instances, autoregulation of flow was significantly enhanced. These results demonstrate that modulation of the myogenic response occurs at postreceptor sites in the smooth muscle cell.

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