Phylogenic Determinants of Cardiovascular Frailty, Focus on Hemodynamics and Arterial Smooth Muscle Cells

2020 ◽  
Vol 100 (4) ◽  
pp. 1779-1837 ◽  
Author(s):  
Jean-Baptiste Michel
Keyword(s):  
Smooth Muscle ◽  
Arterial Pressure ◽  
Smooth Muscle Cells ◽  
Circulatory System ◽  
Muscle Cells ◽  
Wall Structure ◽  
Resistance Arteries ◽  
Hemodynamic Variable ◽  
Arterial Blood ◽  
In Series

The evolution of the circulatory system from invertebrates to mammals has involved the passage from an open system to a closed in-parallel system via a closed in-series system, accompanying the increasing complexity and efficiency of life’s biological functions. The archaic heart enables pulsatile motion waves of hemolymph in invertebrates, and the in-series circulation in fish occurs with only an endothelium, whereas mural smooth muscle cells appear later. The present review focuses on evolution of the circulatory system. In particular, we address how and why this evolution took place from a closed, flowing, longitudinal conductance at low pressure to a flowing, highly pressurized and bifurcating arterial compartment. However, although arterial pressure was the latest acquired hemodynamic variable, the general teleonomy of the evolution of species is the differentiation of individual organ function, supported by specific fueling allowing and favoring partial metabolic autonomy. This was achieved via the establishment of an active contractile tone in resistance arteries, which permitted the regulation of blood supply to specific organ activities via its localized function-dependent inhibition (active vasodilation). The global resistance to viscous blood flow is the peripheral increase in frictional forces caused by the tonic change in arterial and arteriolar radius, which backscatter as systemic arterial blood pressure. Consequently, the arterial pressure gradient from circulating blood to the adventitial interstitium generates the unidirectional outward radial advective conductance of plasma solutes across the wall of conductance arteries. This hemodynamic evolution was accompanied by important changes in arterial wall structure, supported by smooth muscle cell functional plasticity, including contractility, matrix synthesis and proliferation, endocytosis and phagocytosis, etc. These adaptive phenotypic shifts are due to epigenetic regulation, mainly related to mechanotransduction. These paradigms actively participate in cardio-arterial pathologies such as atheroma, valve disease, heart failure, aneurysms, hypertension, and physiological aging.

scholarly journals RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1748
Author(s):  
Eda Demirel ◽  
Caroline Arnold ◽  
Jaspal Garg ◽  
Marius Andreas Jäger ◽  
Carsten Sticht ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Map Kinase ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Genetic Ablation ◽  
Variable Expression ◽  
Arterial Blood

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.

Abstract 477: Diverse Actions of the EP4 Prostaglandin E2 Receptor in Blood Pressure Control

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Marcela Herrera ◽  
Matthew A Sparks ◽  
Beverky H Koller ◽  
Thomas M Coffman
Keyword(s):  
Smooth Muscle ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Smooth Muscle Cells ◽  
Prostaglandin E2 ◽  
Ductus Arteriosus ◽  
Muscle Cells ◽  
High Salt ◽  
Ang Ii ◽  
The Impact

Prostaglandin E2 (PGE2) is a major prostanoid produced by the kidney having the potential to influence renal blood flow, Na excretion, and thus mean arterial pressure (BP). PGE2 actions are mediated by four distinct E-prostanoid (EP) receptor isoforms: EP1-EP4. The EP4 receptor (EP4R) triggers macula densa stimulation of renin, induces vasodilation, and may inhibit epithelial sodium transport. Thus, the impact of EP4Rs on BP may differ with the sites of PGE2 synthesis and pattern of EP4R activation within the kidney. To examine the role of EP4R on BP regulation we generated EP4R-deficient mice. Because deletion of EP4R in utero causes peri-natal mortality due to persistent patent ductus arteriosus, we carried out conditional deletion by crossing EP4flox/flox with a transgenic line with tamoxifen-inducible Cre expression in all tissues. Resting mean arterial pressure (MAP) measured by radiotelemetry was increased by 5±1mm Hg (p<0.05) in mice with total-body EP4R-deficiency (EP4R-TBKO) vs. controls. In addition, EP4R-TBKOs had an exaggerated increase in MAP with high-salt (6% NaCl) feeding (MAP increase: 5±1 vs. 2±1mmHg for controls; p<0.05) and during angiotensin II (Ang II)-dependent hypertension (MAP increase: 37±2 vs. 24±3mmHg for controls; p<0.05). We next hypothesized that exaggerated hypertension in the EP4R-TBKOs was due to elimination of compensatory EP4R-depedent vasodilation mediated by direct actions in vascular smooth muscle cells (VSMCs). Accordingly, we generated mice lacking EP4R in VSMCs (EP4R-SMKOs) using EP4flox/flox and transgenic mice with tamoxifen-inducible expression of Cre limited to smooth muscle cells. In contrast to the EP4R-TBKOs, elimination of EP4R only from VSMC reduced resting MAP by 5±1mm Hg (p<0.04) but did not affect the BP response to high salt feeding (MAP change: 2±1 vs. 2±1 mm Hg; ns) or chronic Ang II infusion (MAP increase: 29±3 vs. 34±4 mm Hg; ns). Thus, the EP4R modulates resting MAP but its specific impact may vary between EP4R populations in different cell lineages. EP4Rs resist the development of salt- and Ang II-dependent hypertension. These anti-hypertensive actions are not mediated by direct effects of EP4R in VSMCs, but may involve EP4R in endothelium, brain, or kidney epithelia.

scholarly journals Caveolin-1 and caveolin-3 regulate Ca2+ homeostasis of single smooth muscle cells from rat cerebral resistance arteries

2007 ◽  
Vol 293 (1) ◽  
pp. H204-H214 ◽  
Author(s):  
T. Kamishima ◽  
T. Burdyga ◽  
J. A. Gallagher ◽  
J. M. Quayle
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Removal Rate ◽  
Muscle Cells ◽  
Amino Acid Residues ◽  
Resistance Arteries ◽  
Inhibitory Peptide ◽  
Caveolin 1 ◽  
Domain Peptide ◽  
Cerebral Resistance

The role of caveolins, signature proteins of caveolae, in arterial Ca2+ regulation is unknown. We investigated modulation of Ca2+ homeostasis by caveolin-1 and caveolin-3 using smooth muscle cells from rat cerebral resistance arteries. Membrane current and Ca2+ transients were simultaneously measured with voltage-clamped single cells. Membrane depolarization triggered Ca2+ current and increased intracellular Ca2+ concentration ([Ca2+]i). After repolarization, elevated [Ca2+]i returned to the resting level. Ca2+ removal rate was determined from the declining phase of the Ca2+ transient. Application of caveolin-1 antibody or caveolin-1 scaffolding domain peptide, corresponding to amino acid residues 82–101 of caveolin-1, significantly slowed Ca2+ removal rate at a measured [Ca2+]i of 250 nM, with little effect at a measured [Ca2+]i of 600 nM. Application of caveolin-3 antibody or caveolin-3 scaffolding domain peptide, corresponding to amino acid residues 55–74 of caveolin-3, also significantly slowed Ca2+ removal rate at a measured [Ca2+]i of 250 nM, with little effect at a measured [Ca2+]i of 600 nM. Likewise, application of calmodulin inhibitory peptide, autocamtide-2-related inhibitory peptide, and cyclosporine A, inhibitors for calmodulin, Ca2+/calmodulin-dependent protein kinase II, and calcineurin, also significantly inhibited Ca2+ removal rate at a measured [Ca2+]i of 250 nM but not at 600 nM. Application of cyclopiazonic acid, a sarcoplasmic reticulum Ca2+ ATPase inhibitor, also significantly inhibited Ca2+ removal rate at a measured [Ca2+]i of 250 nM but not at 600 nM. Our results suggest that caveolin-1 and caveolin-3 are important in Ca2+ removal of resistance artery smooth muscle cells.

A Structure-Based Biomechanical Model for the Effect of Dissolution of Muscle Cells on Pig Arteries: Elastin Associated With Muscle and Extracellular Matrix

2011 ◽  
Author(s):  
Aristotelis Agianniotis ◽  
Alexander Rachev ◽  
Nikos Stergiopulos
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Biomechanical Model ◽  
Muscle Cells ◽  
In Series ◽  
Minor Part ◽  
The Media ◽  
The One ◽  
A Minor

We developed a structure-based model of the arterial wall to explain the effect of dissolution of smooth muscle cells (SMC) on the mechanical behavior of the artery and to obtain a better understanding of the interaction between the different wall components. Pressure-radius curves and dimensions of zero-stress configuration were measured in 5 control and 5 decellularized porcine common carotid arteries. We found that 13% of elastin is associated with the smooth muscle cells (SMC) whereas the rest 87% is associated with the extracellular matrix (ECM). Further, we found that the elastin related to SMC and the one related to the ECM have circumferential prestretches of 2.04 and 0.89, respectively. We conclude that the majority of elastic in the media is linked to ECM and is under compression at zero load, whereas a minor part is linked to VSM and is under tension (SMC related) at its zero load state. Upon chemical dissolution of the muscle cells elastin in series with SMC do not bear load allowing elastin connected to ECM to release its compressive prestress, leading to the expansion of the artery.

scholarly journals TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

2009 ◽  
Vol 297 (3) ◽  
pp. H1096-H1102 ◽  
Author(s):  
Scott Earley ◽  
Thierry Pauyo ◽  
Rebecca Drapp ◽  
Matthew J. Tavares ◽  
Wolfgang Liedtke ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Peripheral Resistance ◽  
Muscle Cells ◽  
Mesenteric Arteries ◽  
Transient Receptor Potential Vanilloid ◽  
Resistance Arteries

Transient receptor potential vanilloid 4 (TRPV4) channels have been implicated as mediators of calcium influx in both endothelial and vascular smooth muscle cells and are potentially important modulators of vascular tone. However, very little is known about the functional roles of TRPV4 in the resistance vasculature or how these channels influence hemodynamic properties. In the present study, we examined arterial vasomotor activity in vitro and recorded blood pressure dynamics in vivo using TRPV4 knockout (KO) mice. Acetylcholine-induced hyperpolarization and vasodilation were reduced by ∼75% in mesenteric resistance arteries from TRPV4 KO versus wild-type (WT) mice. Furthermore, 11,12-epoxyeicosatrienoic acid (EET), a putative endothelium-derived hyperpolarizing factor, activated a TRPV4-like cation current and hyperpolarized the membrane of vascular smooth muscle cells, resulting in the dilation of mesenteric arteries from WT mice. In contrast, 11,12-EET had no effect on membrane potential, diameter, or ionic currents in the mesenteric arteries from TRPV4 KO mice. A disruption of the endothelium reduced 11,12-EET-induced hyperpolarization and vasodilatation by ∼50%. A similar inhibition of these responses was observed following the block of endothelial (small and intermediate conductance) or smooth muscle (large conductance) K+ channels, suggesting a link between 11,12-EET activity, TRPV4, and K+ channels in endothelial and smooth muscle cells. Finally, we found that hypertension induced by the inhibition of nitric oxide synthase was greater in TRPV4 KO compared with WT mice. These results support the conclusion that both endothelial and smooth muscle TRPV4 channels are critically involved in the vasodilation of mesenteric arteries in response to endothelial-derived factors and suggest that in vivo this mechanism opposes the effects of hypertensive stimuli.

scholarly journals Peripheral Coupling Sites Formed by STIM1 Govern the Contractility of Vascular Smooth Muscle Cells

2021 ◽  
Author(s):  
Vivek Krishnan ◽  
Sher Ali ◽  
Albert L. Gonzales ◽  
Pratish Thakore ◽  
Caoimhin S. Griffin ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Transmembrane Domain ◽  
Muscle Cells ◽  
Channel Activity ◽  
Resistance Arteries ◽  
Store Depletion ◽  
Domain Protein

Peripheral coupling between the sarcoplasmic reticulum (SR) and plasma membrane (PM) forms signaling complexes that regulate the membrane potential and contractility of vascular smooth muscle cells (VSMCs), although the mechanisms responsible for these membrane interactions are poorly understood. In many cells, STIM1 (stromal interaction molecule 1), a single transmembrane-domain protein that resides in the endoplasmic reticulum (ER), transiently moves to ER-PM junctions in response to depletion of ER Ca2+ stores and initiates store-operated Ca2+ entry (SOCE). Fully differentiated VSMCs express STIM1 but exhibit only marginal SOCE activity. We hypothesized that STIM1 is constitutively active in contractile VSMCs and maintains peripheral coupling. In support of this concept, we found that the number and size of SR-PM interacting sites were decreased and SR-dependent Ca2+ signaling processes were disrupted in freshly isolated cerebral artery SMCs from tamoxifen-inducible, SMC specific STIM1-knockout (Stim1-smKO) mice. VSMCs from Stim1-smKO mice also exhibited a reduction in nanoscale colocalization between Ca2+-release sites on the SR and Ca2+-activated ion channels on the PM, accompanied by diminished channel activity. Stim1-smKO mice were hypotensive and resistance arteries isolated from them displayed blunted contractility. These data suggest that STIM1 – independent of SR Ca2+ store depletion – is critically important for stable peripheral coupling in contractile VSMCs.

Abstract 378: Cytochrome b5 Reductase 3 Regulates Vascular Smooth Muscle Phenotypic Switching

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Amogha Vijayvargiya ◽  
Anh Nguyen ◽  
Megan P Miller ◽  
Scott Hahn ◽  
Adam C Straub
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cytochrome B5 ◽  
Muscle Cells ◽  
Phenotypic Switching ◽  
Serum Starvation ◽  
Contractile State ◽  
Cytochrome B5 Reductase ◽  
Arterial Blood

Contractile vascular smooth muscle cells (VSMC) play a key role in the regulation of arterial blood vessel tone and cardiovascular health. However, in many vascular diseases, VSMCs undergo a phenotypic switch from a contractile state to a synthetic phenotype, where loss of the contractile markers myosin heavy chain 11 (Myh11), smooth muscle alpha actin (ACTA2) and transgelin (SM22) are observed and proliferation is increased. Recent evidence from our lab demonstrates that cytochrome b5 reductase 3 (Cyb5R3) regulates the redox state of soluble guanylate cyclase to control cGMP levels in VSMCs. Because cGMP modulates protein kinase G activity, a critical kinase that maintains VSMCs in a contractile state, we tested the hypothesis that Cyb5R3 is critical for maintenance of the contractile phenotype. To test this hypothesis, we transduced primary rat aortic smooth muscle cells with non-targeting (NT) or Cyb5R3 shRNA followed by serum starvation for 24, 48, and 72 hours to induce phenotypic switching. After each time point, mRNA measurements of Cyb5R3, Myh11, ACTA2, and SM22 were conducted using RT-PCR. In NT shRNA transduced VSMCs, we observed a significant increase in Cyb5R3, Myh11, ACTA2, and SM22 mRNA, but not in Cyb5R3 knockdown VSMCs. Next, we conducted proliferation studies by serum starving NT shRNA and Cyb5R3 shRNA treated VSMCs for 24 hours followed by stimulation of platelet growth factor BB (PDGF-BB, 40 ng/mL). After 24 hours of PDGF-BB treatment, Cyb5R3 deficient cells showed augmented proliferation compared to control cells measured by 3 H-thymidine incorporation. Together, our data suggest that Cyb5R3 is essential for VSMC phenotypic switching and proliferation, which may unravel a new therapeutic target for treating individuals with cardiovascular disease.

Abstract 524: Extracellular Guanosine Regulates Extracellular Adenosine Levels

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Edwin K Jackson ◽  
Delbert G Gillespie
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Extracellular Adenosine ◽  
Arterial Blood

Extracellular adenosine modulates cardiovascular and renal function. While measuring extracellular purines in biological samples, we observed a correlation between levels of adenosine and guanosine. This observation led us to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels in the cardiovascular and renal systems. Rat preglomerular vascular smooth muscle cells in culture were incubated with adenosine and/or guanosine. In the absence of added adenosine, exogenous guanosine (30 μmol/L) had little effect on extracellular adenosine levels, indicating that extracellular guanosine does not trigger the release or production of adenosine. Without added guanosine and 1 hour after adding 3 μmol/L of exogenous adenosine, extracellular adenosine levels were only 0.125 ± 0.020 μmol/L, indicating rapid disposition of extracellular adenosine by a monolayer of cells. In contrast, extracellular adenosine levels 1 hour after adding 3 μmol/L of adenosine plus guanosine (30 μmol/L) were 1.173 ± 0.061 μmol/L (9-fold higher; p<0.0001), indicating slow disposition of extracellular adenosine in the presence of extracellular guanosine. Extracellular guanosine impeded the disposition of extracellular adenosine not only in preglomerular vascular smooth muscle cells, but also in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts and kidney epithelial cells, as well as in human aortic vascular smooth muscle cells, coronary artery vascular smooth muscle cells and coronary artery endothelial cells. In rats, infusions of guanosine per se had little effect on cardiovascular/renal variables, yet markedly enhanced the effects of co-infusions of adenosine. For example, in control rats, adenosine (0.3 μmol/kg/min) only modestly decreased mean arterial blood pressure (from 114 ± 4 to 100 ± 4 mm Hg). In contrast, in guanosine-treated rats (10 μmol/kg/min), adenosine profoundly decreased blood pressure (from 109 ± 4 to 79 ± 3 mm Hg; p<0.0001 vs non-guanosine treated group). Conclusion: Extracellular guanosine powerfully regulates extracellular adenosine levels by altering adenosine disposition and this occurs in many, perhaps most, cell types in the cardiovascular system and kidneys.

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