Cullin-3 Regulates Vascular Smooth Muscle Function and Arterial Blood Pressure via PPARγ and RhoA/Rho-Kinase

The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gαq/11 and Gαi/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While Rgs5 shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2. Comparable results were obtained with 3D cultured resting VSMCs. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promoted their resting state as evidenced by microarray-based expression profiling and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation, and migration, which was mimicked by selectively inhibiting Gαi/o but not Gαq/11 activity. Collectively, the heterogeneous expression of Rgs5 suggests arterial blood vessel type-specific functions in mouse VSMCs. This comprises inhibition of acute agonist-induced Gαq/11/calcium release as well as the support of a resting VSMC phenotype with low ERK1/2 activity by suppressing the activity of Gαi/o.

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Detrimental Effects of Nearby Construction Activity on Endothelial and Vascular Smooth Muscle Function in Cerebral Arteries of Sprague‐Dawley (S‐D) Rats

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.683.1 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Julian H. Lombard ◽

Maia Terashvili ◽

Kaleigh Kozak ◽

Alison Gifford ◽

Nnamdi Uche ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Muscle Function ◽

Cerebral Arteries ◽

Sprague Dawley ◽

Smooth Muscle Function ◽

Construction Activity

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Fundamental Roles of Axial Stretch in Isometric and Isobaric Evaluations of Vascular Contractility

Journal of Biomechanical Engineering ◽

10.1115/1.4042171 ◽

2019 ◽

Vol 141 (3) ◽

Cited By ~ 4

Author(s):

Alexander W. Caulk ◽

Jay D. Humphrey ◽

Sae-Il Murtada

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Muscle Function ◽

Contractile Function ◽

Contractile Activity ◽

Comparison Of Methods ◽

Axial Stretch ◽

Smooth Muscle Function ◽

In Vivo Loading

Vascular smooth muscle cells (VSMCs) can regulate arterial mechanics via contractile activity in response to changing mechanical and chemical signals. Contractility is traditionally evaluated via uniaxial isometric testing of isolated rings despite the in vivo environment being very different. Most blood vessels maintain a locally preferred value of in vivo axial stretch while subjected to changes in distending pressure, but both of these phenomena are obscured in uniaxial isometric testing. Few studies have rigorously analyzed the role of in vivo loading conditions in smooth muscle function. Thus, we evaluated effects of uniaxial versus biaxial deformations on smooth muscle contractility by stimulating two regions of the mouse aorta with different vasoconstrictors using one of three testing protocols: (i) uniaxial isometric testing, (ii) biaxial isometric testing, and (iii) axially isometric plus isobaric testing. Comparison of methods (i) and (ii) revealed increased sensitivity and contractile capacity to potassium chloride and phenylephrine (PE) with biaxial isometric testing, and comparison of methods (ii) and (iii) revealed a further increase in contractile capacity with isometric plus isobaric testing. Importantly, regional differences in estimated in vivo axial stretch suggest locally distinct optimal biaxial configurations for achieving maximal smooth muscle contraction, which can only be revealed with biaxial testing. Such differences highlight the importance of considering in vivo loading and geometric configurations when evaluating smooth muscle function. Given the physiologic relevance of axial extension and luminal pressurization, we submit that, when possible, axially isometric plus isobaric testing should be employed to evaluate vascular smooth muscle contractile function.

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Hydroxylated 22-Carbon Fatty Acids in Platelet and Vascular Smooth Muscle Function: Interference with TXA2/PGH2 Receptors

Mediators in the Cardiovascular System: Regional Ischemia ◽

10.1007/978-3-0348-7346-8_6 ◽

1995 ◽

pp. 39-45 ◽

Cited By ~ 2

Author(s):

J. W. Karanian ◽

N. Salem

Keyword(s):

Fatty Acids ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Muscle Function ◽

Smooth Muscle Function

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Abstract 107: Cytochrome B5 Reductase 3 Sensitizes Soluble Guanylate Cyclase to Nitric Oxide in Vascular Smooth Muscle

Hypertension ◽

10.1161/hyp.66.suppl_1.107 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Adam C Straub ◽

Anh T Nguyen ◽

Mizanur Rahaman ◽

Stephanie M Mutchler ◽

Megan Miller ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Cytochrome B5 ◽

Heme Iron ◽

Cytochrome B5 Reductase ◽

Arterial Blood

The inability nitric oxide (NO) to stimulate soluble guanylate cyclase (sGC) has been linked to numerous cardiovascular diseases (CVD) including hypertension. While several studies have defined the importance of sGC expression in the cardiovascular system, the basic mechanisms that regulate sGC activity remain incompletely understood. Here, we report for the first time that sGC heme iron redox state, which is essential for NO-induced sGC activation, is regulated by cytochrome B5 reductase 3 (CyB5R3). Genetic knockdown and pharmacological inhibition of CyB5R3 in primary rat vascular smooth muscle cells resulted in a 60% loss in cGMP production. Conversely, the sGC activator Bay 58-2667, which activates oxidized or heme free sGC, reversed these effects. Consistent with our cell culture work, purified protein studies demonstrate that CyB5R3 can directly reduce oxidized sGC heme iron and sensitize sGC to NO. To test the functional importance of Cyb5R3 activity, we cultured mouse thoracodorsal arteries with a pharmacological inhibitor of Cyb5R3 (ZINC 747) and performed vascular reactivity studies using pressure myography. Arteries treated with ZINC 747 showed decreased responsiveness the NO donor DETA-NONOate but increase sensitivity to Bay 58-2667. We then treated mice with 10mg/kg/day of ZINC 747 using osmotic mini pumps, which caused an increase in mean arterial blood pressure (107.5±3.4 vs 131±13.16) measured via radio telemetry. Lastly, translational studies reveal that the CyB5R3 T116S polymorphism with allele frequency 0.23 only in African Americans is unable to reduce sGC and correlates with increased blood pressure. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to NO therapies and new classes of sGC activator medications, we anticipate that these studies may significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (T117S SNP based drug selection).

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