Relaxation Of Vessels Research Articles

Relationships Among Capillary Refill Time, Peripheral Blood Flow Rate, and Fingertip Temperature: Advances in Peripheral Artery Contractility Diagnosis.

Capillary refill time (CRT) is a widely used noninvasive measure of cardiovascular health. Despite its widespread diagnostic utility, it has several limitations, particularly its low sensitivity for certain conditions, because factors such as the contraction and relaxation of distal blood vessels can influence CRT readings. This study was performed to explore the relationships between CRT and distal blood flow. The right hand of each of 10 healthy adult volunteers was cooled to induce blood vessel contraction. CRT, fingertip temperature, and blood flow rate were measured using a custom device, a thermometer, and a laser Doppler blood flow meter, respectively, before and after cooling. Hand cooling significantly decreased blood flow rate and increased CRT. A robust inverse correlation was observed between blood flow rate and CRT, supporting a model where CRT is the time required for blood to flow through a cylindrical pipe. Furthermore, CRT showed a significant negative correlation with fingertip temperature. Most participants had high correlation coefficients, although two showed lower values. However, all data points exhibited a linear relationship, with the slopes of the regression lines between CRT and temperature varying among participants. These results suggested that the slope between CRT and fingertip temperature indicates individual differences in arterial contractility. These findings could improve the diagnostic utility of CRT in assessing vascular health, including arterial age and Raynaud's phenomenon, based on the contractility of peripheral arteries.

Follistatin lowers blood pressure and improves vascular structure and function in essential and secondary hypertension.

Hypertension is characterized by resistance artery remodeling driven by oxidative stress and fibrosis. We previously showed that an activin A antagonist, follistatin, inhibited renal oxidative stress and fibrosis in a model of hypertensive chronic kidney disease. Here, we investigate the effects of follistatin on blood pressure and vascular structure and function in models of essential and secondary hypertension. 5/6 nephrectomised mice, a model of secondary hypertension, were treated with either exogenous follistatin or with a follistatin miRNA inhibitor to increase endogenous follistatin for 9 weeks. Blood pressure in mice was measured by tail cuff. Spontaneously hypertensive rats, a model of essential hypertension, were treated with follistatin for 8 weeks. Wistar Kyoto (WKY) rats were used as the normotensive control. Blood pressure in rats was measured by radiotelemetry. Mouse superior mesenteric arteries and rat first branch mesenteric arteries were isolated for structural and functional analyses. In both models, follistatin significantly lowered blood pressure and improved vascular structure, decreasing medial thickness and collagen content. Follistatin also reduced agonist-induced maximum contraction and improved endothelium-dependent relaxation. Increased vessel oxidative stress was attenuated by follistatin in both models. In ex vivo WKY vessels, activin A increased oxidative stress, augmented constriction, and decreased endothelium-dependent relaxation. Inhibition of oxidative stress restored vessel relaxation. This study demonstrates that follistatin lowers blood pressure and improves vascular structure and function in models of essential and secondary hypertension. Effects were likely mediated through its inhibition of activin A and oxidative stress. These data suggest a potential therapeutic role for follistatin as a novel antihypertensive agent. Follistatin, through antagonization of activin A, inhibits oxidative stress and improves vascular structure and function in resistance arteries from models of essential and secondary HTN. FST decreases collagen content and vascular ROS. Functionally, FST improves endothelium-dependent relaxation and decreases maximal vasoconstriction. Improved resistance artery structure and function are correlated with a decrease in BP in both models.

Low Calcium-High Magnesium Krebs-Henseleit Solution Combined with Adenosine and Lidocaine Improved Rat Aortic Function and Structure Following Cold Preservation.

Background and objectives: The main problem of vascular preservation is the maintenance of vessel graft quality and function following extended storage. Conventional preservation solutions such as histidine-tryptophan-ketoglutarate (HTK) solution, Phosphate-Buffer Solution (PBS), or sodium chloride 0.9% has been shown to be inadequate in preserving vascular physiological function after 3 days of cold storage. This study aimed to evaluate whether adenosine and lidocaine (AL) in a modified Krebs-Henseleit (KH) solution can preserve the function and histological structure of rat aortic rings after 6 days. Materials and Methods: Thirty-five aortic rings from male Wistar rats (200-300 g) were harvested and immediately immersed in one of the assigned cold preservation solutions: standard KH, modified KH (mod KH) with lower calcium (Ca2+) and higher magnesium content (Mg2+) with or without adenosine and lidocaine (mod KH-AL), and modified KH with AL, insulin, and melatonin (Mod KH-ALMI). The contraction and relaxation function of the aortic rings were examined using an isometric force transducer after 6 days of cold preservation. Hematoxylin and eosin staining were used to analyze the rings' histological structure. Results: Vascular contraction and relaxation functions were severely affected after a 6-day cold storage period in standard KH. Modifying the KH solution by reducing the Ca2+ and increasing the Mg2+ levels greatly recovered the vessel functions. The addition of AL or ALMI to the modified KH did not further recover vascular contractility. However, only the addition of AL to the modified KH increased the ACh-induced relaxation at 6 days when compared to the conventional KH, suggesting that endothelium preservation is improved. From histological analysis, it was found that the addition of AL but not ALMI further improved the endothelial lining and the structure of the elastic membrane layers of the preserved vessels after 6 days of cold preservation. Conclusions: The addition of AL to low calcium-high magnesium KH solution significantly enhanced endothelial preservation and improved endothelial-induced relaxation of preserved vessels after 6 days of cold storage.

Nfluence of extracellular acidosis on the functional contribution of KATP and TASK-1 potassium channels to the regulation of vascular tone in early postnatal ontogenesis

The activity of many proteins and, as a result, of the mechanisms of vascular tone regulation depends on pH. A decrease of pH (uncompensated acidosis), usually causes relaxation of blood vessels, which has been studied in sufficient detail for an adult, matured organism. However, the effect of acidosis on the mechanisms of vascular tone regulation in the early postnatal period remains almost completely unexplored. The aim of this work was to study the effect of extracellular metabolic acidosis on the functional contribution of KATP and TASK-1 potassium channels to the regulation of vascular tone in early postnatal period. We modeled extracellular metabolic acidosis (pH 6.8, equimolar replacement of NaHCO3 with NaCl in solution) and studied isometric contractile responses of the saphenous artery in rats aged 3–4 months and rat pups aged 12–15 days. Arterial contraction to the α1-adrenergic agonist methoxamine at pH 6.8 was reduced compared to normal pH 7.4 in both 3–4-month-old and 12–15-day-old rats. The KATP channel blocker glibenclamide did not change the arterial responses to methoxamine, neither at pH 7.4 nor at pH 6.8 in any of the age groups. The TASK-1 channel blocker AVE1231 did not alter arterial contractile responses at any pH in 3–4-month-old rats. However, in 12–15-day-old rat pups, the increase in contractile responses to methoxamine under the influence of AVE1231 was less at pH 6.8 than at pH 7.4. Thus, the results of this work demonstrate that acidosis reduces the contractile activity of the arteries of 3–4-month-old animals and animals during early postnatal ontogenesis, while in the latter, the anticontractile role of TASK-1 channels decreases, and KATP channels do not affect the regulation of vascular tone, either under normal, or at acidic pH in any of the age groups.

The interplay of hydrogen sulfide and microRNAs in cardiovascular diseases: insights and future perspectives.

Hydrogen sulfide (H2S) is recognized as the third gasotransmitter, after nitric oxide (NO) and carbon monoxide (CO). It is known for its cardioprotective properties, including the relaxation of blood vessels, promotion of angiogenesis, regulation of myocardial cell apoptosis, inhibition of vascular smooth muscle cell proliferation, and reduction of inflammation. Additionally, abnormal H2S generation has been linked to the development of cardiovascular diseases (CVD), such as pulmonary hypertension, hypertension, atherosclerosis, vascular calcification, and myocardial injury. MicroRNAs (miRNAs) are non-coding, conserved, and versatile molecules that primarily influence gene expression by repressing translation and have emerged as biomarkers for CVD diagnosis. Studies have demonstrated that H2S can ameliorate cardiac dysfunction by regulating specific miRNAs, and certain miRNAs can also regulate H2S synthesis. The crosstalk between miRNAs and H2S offers a novel perspective for investigating the pathophysiology, prevention, and treatment of CVD. The present analysis outlines the interactions between H2S and miRNAs and their influence on CVD, providing insights into their future potential and advancement.

Purinergic regulation of pulmonary vascular tone.

Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca2+ levels. The P2X subtype receptors facilitate extracellular Ca2+ influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca2+ release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A2B receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y1, P2Y2, and P2Y4 receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.

Inside the Biology of the β3-Adrenoceptor.

Since the first discovery in 1989, the β3-adrenoceptor (β3-AR) has gained great attention because it showed the ability to regulate many physiologic and metabolic activities, such as thermogenesis and lipolysis in brown and white adipose tissue, respectively (BAT, WAT), negative inotropic effects in cardiomyocytes, and relaxation of the blood vessels and the urinary bladder. The β3-AR has been suggested as a potential target for cancer treatment, both in adult and pediatric tumors, since under hypoxia its upregulation in the tumor microenvironment (TME) regulates stromal cell differentiation, tumor growth and metastases, signifying that its agonism/antagonism could be useful for clinical benefits. Promising results in cancer research have proposed the β3-AR being targeted for the treatment of many conditions, with some drugs, at present, undergoing phase II and III clinical trials. In this review, we report the scientific journey followed by the research from the β3-Ars' discovery, with focus on the β3-Ars' role in cancer initiation and progression that elects it an intriguing target for novel antineoplastic approaches. The overview highlights the great potential of the β3-AR, both in physiologic and pathologic conditions, with the intention to display the possible benefits of β3-AR modulation in cancer reality.

Red light mediates the exocytosis of vasodilatory vesicles from cultured endothelial cells: a cellular, and ex vivo murine model

We have previously established that 670 nm energy induces relaxation of blood vessels via an endothelium derived S-nitrosothiol (RSNO) suggested to be embedded in vesicles. Here, we confirm that red light facilitates the exocytosis of this vasodilator from cultured endothelial cells and increases ex vivo blood vessel diameter. Ex vivo pressurized and pre-constricted facial arteries from C57Bl6/J mice relaxed 14.7% of maximum diameter when immersed in the medium removed from red-light exposed Bovine Aortic Endothelial Cells. In parallel experiments, 0.49 nM RSNO equivalent species was measured in the medium over the irradiated cells vs dark control. Electron microscopy of light exposed endothelium revealed significant increases in the size of the Multi Vesicular Body (MVB), a regulator of exosome trafficking, while RSNO accumulated in the MVBs as detected with immunogold labeling electron microscopy (1.8-fold of control). Moreover, red light enhanced the presence of F-actin related stress fibers (necessary for exocytosis), and the endothelial specific marker VE-cadherin levels suggesting an endothelial origin of the extracellular vesicles. Flow cytometry coupled with DAF staining, an indirect sensor of nitric oxide (NO), indicated significant amounts of NO within the extracellular vesicles (1.4-fold increase relative to dark control). Therefore, we further define the mechanism on the 670 nm light mediated traffic of endothelial vasodilatory vesicles and plan to leverage this insight into the delivery of red-light therapies.Graphical abstract

Nitric oxide, endothelium-derived hyperpolarizing factor, and smooth muscle-dependent mechanisms contribute to magnesium-dependent vascular relaxation in mouse arteries.

Magnesium (Mg2+ ) is a vasorelaxant. The underlying physiological mechanisms driving this vasorelaxation remain unclear. Studies were designed to test the hypothesis that multiple signaling pathways including nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in endothelial cells as well as Ca2+ antagonization and TRPM7 channels in vascular smooth muscle cells mediate Mg2+ -dependent vessel relaxation. To uncover these mechanisms, force development was measured exvivo in aorta rings from mice using isometric wire myography. Concentration responses to Mg2+ were studied in intact and endothelium-denuded aortas. Key findings were confirmed in second-order mesenteric resistance arteries perfused exvivo using pressure myography. Effects of Mg2+ on NO formation were measured in Chinese Hamster Ovary (CHO) cells, isolated mesenteric vessels, and mouse urine. Mg2+ caused a significant concentration-dependent relaxation of aorta rings. This relaxation was attenuated significantly in endothelium-denuded aortas. The endothelium-dependent portion was inhibited by NO and cGMP blockade but not by cyclooxygenase inhibition. Mg2+ stimulated local NO formation in CHO cells and isolated mesenteric vessels without changing urinary NOx levels. High extracellular Mg2+ augmented acetylcholine-induced relaxation. SKCa and IKCa channel blockers apamin and TRAM34 inhibited Mg2+ -dependent relaxation. The endothelium-independent relaxation in aorta rings was inhibited by high extracellular Ca2+ . Combined blockade of NO, SKCa , and IKCa channels significantly reduced Mg2+ -dependent dilatation in mesenteric resistance vessels. In mouse conductance and resistance arteries Mg2+ -induced relaxation is contributed by endothelial NO formation, EDHF pathways, antagonism of Ca2+ in smooth muscle cells, and additional unidentified mechanisms.

Oxidative Stress: Use of Alternative Therapeutic Agents

Kalonji seeds are a powerhouse of crude fibers, amino acids, iron, sodium, calcium, and potassium. Kalonji is also rich in vitamins that include – Vitamin A, Vitamin B, Vitamin B12, Niacin, and Vitamin C. Kalonji oil is much better than other oil as it contains essential fatty acids, vitamins, and minerals. It comprised approximately 17% protein, 26% carbohydrates, and 57% plant fats and oils. Apart from drugs various substances and life style changes are being advised to correct oxidative stress burden in human body. Analysis of the lipid content in the oxidatively modified LDL from hyper lipidemic patients revealed that the level of lysophosphatidylcholine was greatly elevated, and the high level of the lysolipid was shown to impair the endothelium-dependent relaxation of the blood vessels. In alllopathy blood lipid levels are normalized by statins, fibrates, niacin and bile acid binding resins (BABRs). All of these allopathy related drugs have low compliance ranges from mild compliance due to metalic taste of BABRs to severe side effects like rhabdomyolysis by fibrates and statins. Cardiovascular diseases are leading cause of death in western and eastern countries of the world. Hyperlipidemia is one of the strong risk fractions for heart diseases. To evaluate hypolipidemic drugs efficacy, the study was conducted at Ghurki trust teaching hospital, Lahore Pakistan from January 2020 to August 2020. Ninty hyperlipidemic patients were selected from cardiology and medical wards of the hospital. They were divided in three groups, one at placebo therapy, another on Kalonji and third one on Vitamin B3. After one and half month, significant changes (p value ranging from <0.05 to <0.001) were observed in their LDL and HDL-cholesterol. Conclusion of the study was to recommend use of herbal medicine and vitamin B3 for prevention of any heart diseases with good patient compliance. KEY WORDS: kalonji, LDL cholesterol, HDL cholesterol, blood vessels.

Mechanism of Action of Many Drugs Depend on Enzyme Inhibition

Enzyme inhibition is an important process in the mode of action of many drugs used in the treatment of various diseases. Antibiotics, anti-hypertensive agents, anti-hyperlipidaemic, anti-glaucoma, and anti-malarial drugs act on specific enzymes, leading to bacteriostatic or bactericidal effects, lower blood pressure, reduce cholesterol levels, and cause smooth muscle relaxation of blood vessels. Understanding the mode of action of these drugs and how they affect enzymes is crucial for the development of new drugs and the optimization of existing therapies. This article highlights some various drugs that act through enzyme inhibition and their mechanisms of action.

The Role of Reactive Oxygen Species in the Regulation of Blood Vessel Tone in Perinatal and Early Postnatal Ontogenesis

Reactive oxygen species (ROS) have been considered for many years as negative regulators in the cardiovascular system. Indeed, excessive production of ROS characterizes many cardiovascular diseases. The damaging effect of ROS can be especially pronounced in a newborn organism, since during this period their contractile effect in pulmonary arteries remains as high as in the pre-term fetus arteries and the antioxidant systems have not yet formed. Therefore, in the first hours and days of independent life, pulmonary arteries tend to contract, primarily due to the low bioavailability of endothelial NO, which increases the risk of developing pulmonary hypertension in newborns. At the same time, during the perinatal period, ROS play an important role in the adaptive reactions of the circulatory system. ROS provide occlusion of the ductus arteriosus and separation of the pulmonary and systemic circulations soon after birth, and also contribute to the contraction of peripheral vessels during hypoxia, which often accompanies the delivery, and therefore provide priority blood supply to the brain in these conditions. The vasomotor effect of ROS is also pronounced in early postnatal ontogenesis, but it has a different character. In the first weeks of life, the action of ROS serves as one of the mechanisms for increasing endothelium-dependent relaxation of pulmonary vessels. In addition, during early postnatal ontogeny, ROS may play an important role in the regulation of systemic vascular tone. This review outlines the current understanding of the vasomotor role of ROS in the vessels of the pulmonary and systemic circulation and considers the mechanisms of ROS effects on the functioning of vascular endothelial and smooth muscle cells in the perinatal and early postnatal periods.

G6PD Deficiency: Exploring the Relationship with Different Medical Disorders

G6PD deficiency (G6PDD) is associated with oxidative stress resulting from an imbalance between reactive oxygen species (ROS) production and the body's ability to counteract. In this review, we explore the adverse effects of G6PDD on diverse physiological processes and disease outcomes. Past studies have demonstrated the association between G6PDD and various other diseases, indicating a link between G6PDD to heightened oxidative stress by accelerating virus replication, worsening infection severity, and weakening the body's defense mechanisms. Such stress is critical in the destruction of red blood cells (RBCs) during infections and has a detrimental impact on redox signaling, ultimately impacting cell health and promoting cancer development. Furthermore, it impairs endothelial function by lowering the nitric oxide (NO) level and increasing stress, resulting in detrimental cardiac consequences and reduced myocardial antioxidant capacity. Because ROS contributes to inflammation, this imbalance causes conditions such as early atherosclerosis. It also compromises the functionality of NO-regulated bronchodilators and conditions such as G6PDD exacerbate the risks of kidney damage. Elevated ROS levels can also induce harm in retinal tissues, blood vessels, brain cells, and Beta-cells, hence quickening the progression of diseases like Diabetic Retinopathy. Furthermore, oxidative stress plays a significant role in cerebral ischemic pathogenesis, contributing to neurodegenerative disorders. Additionally, decreased NADPH level is vital for NO synthesis as it can impact blood vessel relaxation and can potentially lead to ischaemic priapism. Investigating the association between G6PDD and other medical conditions is crucial as it helps to identify possible approaches to mitigate oxidative stress, thereby preventing associated complications and diseases, particularly in situations where current treatment options are insufficient.

Reduced Nitric Oxide Synthase Involvement in Aigamo Duck Basilar Arterial Relaxation.

The basilar arterial endothelium mediates blood vessel relaxation partly through the release of nitric oxide (NO). Apoptosis of cerebrovascular endothelial cells is linked to a high mortality rate in chickens infected with the highly pathogenic avian influenza virus, but interestingly, ducks exhibit a greater resistance to this virus. In this study, we examined the responsiveness of duck basilar arteries (BAs) to various vasoactive substances, including 5-hydroxytryptamine (5-HT), histamine (His), angiotensin (Ang) II, noradrenaline (NA), acetylcholine (ACh), and avian bradykinin ornithokinin (OK), aiming to characterize the receptor subtypes involved and the role of endothelial NO in vitro. Our findings suggest that arterial contraction is mediated with 5-HT1 and H1 receptors, while relaxation is induced with β3-adrenergic and M3 receptors. Additionally, OK elicited a biphasic response in duck BAs, and Ang II had no effect. Endothelial NO appears to be crucial in relaxation mediated with M3 and OK receptors but not β3-adrenergic receptors in the duck BA. The reduced endothelial NO involvement in the receptor-mediated relaxation response in duck BAs represents a clear difference from the corresponding response reported in chicken BAs. This physiological difference may explain the differences in lethality between ducks and chickens when vascular endothelial cells are infected with the virus.

HUBUNGAN KEPATUHAN MINUM OBAT TERHADAP KONTROL TEKANAN DARAH PASIEN HIPERTENSI DI PUSKESMAS MANGGIS PROVINSI BALI

Hypertension is a chronic disease that requires long-term treatment. This has an impact on the size of national health financing. In an effort to anticipate costs related to complications, it is necessary to evaluate treatment adherence in the short and long term. This study aims to analyze the relationship between medication adherence and blood pressure control as a short-term outcome of hypertension management at the primary care level. The research method uses a cross sectional design. The research was conducted at the Manggis Health Center with a total sample of 32 people. The sampling technique used is purposive sampling. The measurements used demographic questionnaires, observation sheets for blood pressure checks, and the MMAS-8 questionnaire in Indonesian. Statistical test resultsusing Chi square found p = 0,016 (p<0,05) so there is a relationship between medication adherence and blood pressure control in hypertensive patients. The therapeutic effect of ACE inhibitor and calcium channel blocker directly make the blood vessels relax and wider. The characteristics of hypertensive patients at the Manggis Health Center are mostly the elderly population, women, most do not smoke, and do not have comorbid diabetes. However, proactive prognosis projection is needed. The conclusion in this study is that there is a relationship between medication adherence and blood pressure control in hypertensive patients at the Manggis Health Center.

The effect of temperature on vascular smooth muscle: cooling-induced vasodilation in deep arteries and veins.

Blood vessels in the cardiovascular system include arteries and veins, which are responsible for moving blood to and from tissues around the body. Our previous studies showed that cooling induces relaxation of arteries. The aim of this study is to investigate the effect of cooling on both arteries and veins pairs. Isometric tension was recorded in rat artery ring preparations (aorta, carotid, pulmonary arteries) and their vein pairs (vena cava, jugular, pulmonary veins) in organ baths during stepwise cooling from 37 to 4°C. Cooling responses were tested before and after the addition of various standard agents. The possibility of the presence of a cooling-relaxed substance and the influence of endothelium were also examined. Cooling-induced relaxation of both arteries and veins and the degree of relaxation were inversely proportional to the temperature. The cooling response was highest in arteries than their respective paired veins. The relaxation response was not endothelium dependent or affected with neurogenic mechanism (autonomic blockers or tetrodotoxin). Additionally, it was not changed by alterations of extra- or intra-cellular calcium transfer, and no relaxant substance was released from vascular smooth muscles during cooling. The study showed that cooling induces relaxation of both arteries and veins. Our results suggested that the effect of cooling could be through a thermal receptor in the vascular smooth muscle. Therefore, cold temperature can act as an agonist and increase in cooling temperature behaves as increase in concentration of the agonist. This study contributes to a better understanding of the mechanisms behind cooling-induced relaxation of blood vessels, which may have implications for the treatment of cardiovascular diseases.

Downregulation of connexin 43-based gap junctions underlies propofol-induced excessive relaxation in hypertensive vascular smooth muscle cells

BackgroundPostinduction hypotension caused by propofol remains a non-negligible problem for anesthesiologists, and is especially severe in chronic hypertensive patients with long-term vasoconstriction and decreased vascular elasticity. The functional change in gap junctions composed of Cx43 (Cx43-GJs) is reported as the biological basis of synchronized contraction or relaxation of blood vessels. Thus, we investigated the role of Cx43-GJs in propofol-induced dramatic blood pressure fluctuations in chronic hypertensive patients, and their internal mechanisms.MethodsHuman umbilical artery smooth muscle cells (HUASMCs) were pretreated with long-term angiotensin II (Ang II), with or without propofol, to simulate the contraction and relaxation of normal and hypertensive VSMCs during anesthesia induction. The levels of F-actin polymerization and MLC2 phosphorylation were used as indicators to observe the contraction and relaxation of HUASMCs. Different specific activators, inhibitors and siRNAs were used to explore the role of Cx43-GJs and Ca2+ as well as the RhoA/ LIMK2/cofilin and RhoA/MLCK signaling pathways in the contraction and relaxation of normal and hypertensive HUASMCs.ResultsBoth F-actin polymerization and MLC2 phosphorylation were significantly enhanced in Ang II-pretreated HUASMCs, along with higher expression of Cx43 protein and stronger function of Cx43-GJs than in normal HUASMCs. However, with propofol administration, similar to Gap26 and Cx43-siRNA, the function of Cx43-GJs in Ang II-pretreated HUASMCs was inhibited compared with that in normal HUASMCs, accompanied by a larger decrease in intracellular Ca2+ and the RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways. Eventually F-actin polymerization and MLC2 phosphorylation were more dramatically decreased. However, these effects could be reversed by RA with enhanced Cx43-GJ function.ConclusionLong-term exposure to Ang II significantly enhanced the expression of the Cx43 protein and function of Cx43-GJs in HUASMCs, resulting in the accumulation of intracellular Ca2+ and the activation of its downstream RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways, which maintained HUASMCs in a state of excessive-contraction. With inhibition of Cx43-GJs by propofol in Ang II-pretreated HUASMCs, intracellular Ca2+ and its downstream signaling pathways were dramatically inhibited, which ultimately excessively relaxed HUASMCs. This is the reason why the blood pressure fluctuation of patients with chronic hypertension was more severe after receiving propofol induction.9gEgDUsF4_-ddhb1iAhQGKVideo

Independent endothelial functions of PIEZO1 and TRPV4 in hepatic portal vein and predominance of PIEZO1 in mechanical and osmotic stress.

PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen. Wall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non-disruptive tag in native PIEZO1 or endothelial-specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively. PIEZO1 activation leads to nitric oxide synthase- and endothelium-dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium-dependent but independent of nitric oxide synthase. The TRPV4-mediated contraction is suppressed by inhibitors of phospholipase A2 and cyclooxygenases and mimicked by prostaglandin E2 , suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo-osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses. The portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures.

The FAT1 Cadherin Drives Vascular Smooth Muscle Cell Migration.

Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly to the progression of several cardiovascular diseases. VSMC migration specifically supports atherosclerosis, restenosis after catheter-based intervention, transplant vasculopathy, and vascular remodeling during the formation of aneurysms. The atypical cadherin FAT1 is expressed robustly in activated VSMCs and promotes their migration. A positive role of FAT1 in the migration of other cell types, including neurons, fibroblasts, podocytes, and astrocyte progenitors, has also been described. In cancer biology, however, the effect of FAT1 on migration depends on the cancer type or context, as FAT1 either suppresses or enhances cancer cell migration and invasion. With this review, we describe what is known about FAT1's effects on cell migration as well as the factors that influence FAT1-dependent migration. In VSMCs, these factors include angiotensin II, which activates FAT1 expression and cell migration, and proteins of the Atrophin family: Atrophin-1 and the short isoform of Atrophin-2, which promote VSMC migration, and the long isoform of Atrophin-2, which exerts negative effects on FAT1-dependent VSMC migration.

Physical Training vs. Perindopril Treatment on Arterial Stiffening of Spontaneously Hypertensive Rats: A Proteomic Analysis and Possible Mechanisms.

(1) Background: Arterial stiffness is an important predictor of cardiovascular events. Perindopril and physical exercise are important in controlling hypertension and arterial stiffness, but the mechanisms are unclear. (2) Methods: Thirty-two spontaneously hypertensive rats (SHR) were evaluated for eight weeks: SHRC (sedentary); SHRP (sedentary treated with perindopril-3 mg/kg) and SHRT (trained). Pulse wave velocity (PWV) analysis was performed, and the aorta was collected for proteomic analysis. (3) Results: Both treatments determined a similar reduction in PWV (-33% for SHRP and -23% for SHRT) vs. SHRC, as well as in BP. Among the altered proteins, the proteomic analysis identified an upregulation of the EH domain-containing 2 (EHD2) protein in the SHRP group, required for nitric oxide-dependent vessel relaxation. The SHRT group showed downregulation of collagen-1 (COL1). Accordingly, SHRP showed an increase (+69%) in the e-NOS protein level and SHRT showed a lower COL1 protein level (-46%) compared with SHRC. (4) Conclusions: Both perindopril and aerobic training reduced arterial stiffness in SHR; however, the results suggest that the mechanisms can be distinct. While treatment with perindopril increased EHD2, a protein involved in vessel relaxation, aerobic training decreased COL1 protein level, an important protein of the extracellular matrix (ECM) that normally enhances vessel rigidity.