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GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure.

ABSTRACT: Vascular resistance is a major determinant of BP and is controlled, in large part, by RhoA-dependent smooth muscle cell (SMC) contraction within small peripheral arterioles and previous studies from our lab indicate that GRAF3 is a critical regulator of RhoA in vascular SMC. The elevated contractile responses we observed in GRAF3 deficient vessels coupled with the hypertensive phenotype provided a mechanistic link for the hypertensive locus recently identified within the GRAF3 gene. On the basis of our previous findings that the RhoA signaling axis also controls SMC contractile gene expression and that GRAF3 expression was itself controlled by this pathway, we postulated that GRAF3 serves as an important counter-regulator of SMC phenotype. Indeed, our new findings presented herein indicate that GRAF3 expression acts as a pressure-sensitive rheostat to control vessel tone by both reducing calcium sensitivity and restraining expression of the SMC-specific contractile proteins that support this function. Collectively, these studies highlight the potential therapeutic value of GRAF3 in the control of human hypertension.

SUBMITTER: Bai X

PROVIDER: S-EPMC7549679 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure.

Bai Xue X Mangum Kevin K Kakoki Masao M Smithies Oliver O Mack Christopher P CP Taylor Joan M JM

Small GTPases 20180107 3

Vascular resistance is a major determinant of BP and is controlled, in large part, by RhoA-dependent smooth muscle cell (SMC) contraction within small peripheral arterioles and previous studies from our lab indicate that GRAF3 is a critical regulator of RhoA in vascular SMC. The elevated contractile responses we observed in GRAF3 deficient vessels coupled with the hypertensive phenotype provided a mechanistic link for the hypertensive locus recently identified within the GRAF3 gene. On the basis ...[more]

PMID: 29099324

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Project description:Rationale: Antral peristalsis is responsible for gastric emptying. Its failure is called gastroparesis and often caused by dysfunction of enteric neurons and interstitial cells of Cajal (ICC). Current treatment options, including gastric electrical stimulation, are non-satisfying and may improve symptoms but commonly fail to restore gastric emptying. Herein, we explore direct optogenetic stimulation of smooth muscle cells (SMC) via the light-gated non-selective cation channel Channelrhodopsin2 (ChR2) to control gastric motor function. Methods: We used a transgenic mouse model expressing ChR2 in fusion with eYFP under the control of the chicken-β-actin promoter. We performed patch clamp experiments to quantify light-induced currents in isolated SMC, Ca2+ imaging and isometric force measurements of antral smooth muscle strips as well as pressure recordings of intact stomachs to evaluate contractile responses. Light-induced propulsion of gastric contents from the isolated stomach preparation was quantified in video recordings. We furthermore tested optogenetic stimulation in a gastroparesis model induced by neuronal- and ICC-specific damage through methylene blue photo-toxicity. Results: In the stomachs, eYFP signals were restricted to SMC in which blue light (460 nm) induced inward currents typical for ChR2. These depolarizing currents led to contractions in antral smooth muscle strips that were stronger than those triggered by supramaximal electrical field stimulation and comparable to those evoked by global depolarization with high K+ concentration. In the intact stomach, panoramic illumination efficiently increased intragastric pressure achieving 239±46% (n=6) of the pressure induced by electrical field stimulation and triggered gastric transport. Within the gastroparesis model, electric field stimulation completely failed but light still efficiently generated pressure waves. Conclusions: We demonstrate direct optogenetic stimulation of SMC to control gastric contractility. This completely new approach could allow for the restoration of motility in gastroparesis in the future.

Project description:PurposeWe evaluated the impact of increasing tidal volume (V (t)), decreased chest wall compliance, and left ventricular (LV) contractility during intermittent positive-pressure ventilation (IPPV) on the relation between pulse pressure (PP) and LV stroke volume (SV(LV)) variation (PPV and SVV, respectively), and intrathoracic blood volume (ITBV) changes.MethodsSixteen pentobarbital-anesthetized thoracotomized mongrel dogs were studied both before and after propranolol-induced acute ventricular failure (AVF) (n = 4), with and without chest and abdominal pneumatic binders to decrease chest wall compliance (n = 6), and during V (t) of 5, 10, 15, and 25 ml/kg (n = 6). SV(LV) and right ventricular stroke volume (SV(RV)) were derived from electromagnetic flow probes around aortic and pulmonary artery roots. Arterial pressure was measured in the aorta using a fluid-filled catheter. Arterial PPV and SVV were calculated over three breaths as (max - min)/[(max + min)/2]. ITBV changes during ventilation were inferred from the beat-to-beat volume differences between SV(RV) and SV(LV).ResultsArterial PP and SV(LV) were tightly correlated during IPPV under all conditions (r (2) = 0.85). Both PPV and SVV increased progressively as V (t) increased and with thoraco-abdominal binding, and tended to decrease during AVF. SV(RV) phasically decreased during inspiration, whereas SV(LV) phasically decreased 2-3 beats later, such that ITBV decreased during inspiration and returned to apneic values during expiration. ITBV decrements increased with increasing V (t) or with thoraco-abdominal binding, and decreased during AVF owing to variations in SV(RV), such that both PPV and SVV tightly correlated with inspiration-associated changes in SV(RV) and ITBV.ConclusionArterial PP and SV(LV) are tightly correlated during IPPV and their relation is not altered by selective changes in LV contractility, intrathoracic pressure, or V (t). However, contractility, intrathoracic pressure, and V (t) directly alter the magnitude of PPV and SVV primarily by altering the inspiration-associated decreases in SV(RV) and ITBV.

Dataset Information

GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure.

Publications

GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure.

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