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Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (20 February 2018) | Viewed by 58013

Special Issue Editors

Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35–1, Towada, Aomori 034–8628, Japan
Interests: vascular biology; hypertension; atherosclerosis; adipocytokine; diabetes-related vascular dysfunction; hypertrophy; heart failure; pulmonary arterial hypertension; calmodulin-related proteins; cardiovascular pharmacology
Special Issues, Collections and Topics in MDPI journals
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
Interests: vascular biology; endothelial dysfunction; endothelium-derived factors; diabetes; hypertension; vascular smooth muscle; chronic inflammation; oxidative stress; endoplasmic reticulum stress; aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular active substances contribute to the maintenance of cardiovascular homeostasis. Conversely, disturbances might potentially induce cardiovascular diseases (CVDs). For example, continuous production of endothelium-derived substances, including nitric oxide and vasodilating prostanoids, is protective against CVDs, such as hypertension, atherosclerosis, and ischemic CVDs, while the increased production of endithelium-derived substances, including constrictive prostanoids and endothelin-1, potentially promote CVDs. Thus, the balance of cardiovascular active substances is very important for the maintenance of cardiovascular homeostasis. In addition to such classical substances, many other novel cardiovascular active substances, such as adipocyte-derived cytokine (adipocytokine) and matricryptins (active fragments of extracellular matrix), have been identified. Moreover, cellular events, including endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis induced by the abovementioned substances or inflammation, also play important roles in the development of CVDs. In this Special Issue, we aim at collecting current knowledge of those cardiovascular active substances and cellular events, summarize their mechanisms of actions, on both cardiovascular physiology and pathophysiology, and explore their potential applications in the treatment and diagnosis of CVDs.

Prof. Dr. Hideyuki Yamawaki
Dr. Takayuki Matsumoto
Guest Editors

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Keywords

  • hypertension

  • atherosclerosis

  • diabetes-related cardiovascular diseases

  • pulmonary arterial hypertension

  • ischemic cardiovascular diseases

  • cardiac hypertrophy/failure

  • endothelium

  • vascular smooth muscle

  • cardiac cells

  • adipocytokine

  • extracellular matrix

  • endoplasmic reticulum stress

  • mitochondrial dysfunction

  • gestational hypertension

  • chronic inflammation

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Published Papers (10 papers)

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Research

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15 pages, 4330 KiB  
Article
Endostatin Stimulates Proliferation and Migration of Myofibroblasts Isolated from Myocardial Infarction Model Rats
by Akira Sugiyama, Yuka Hirano, Muneyoshi Okada and Hideyuki Yamawaki
Int. J. Mol. Sci. 2018, 19(3), 741; https://doi.org/10.3390/ijms19030741 - 06 Mar 2018
Cited by 24 | Viewed by 4578
Abstract
Myofibroblasts contribute to the healing of infarcted areas after myocardial infarction through proliferation, migration, and production of extracellular matrix (ECM). Expression of endostatin, a cleaved fragment of type XVIII collagen, increases in the heart tissue of an experimental myocardial infarction model. In the [...] Read more.
Myofibroblasts contribute to the healing of infarcted areas after myocardial infarction through proliferation, migration, and production of extracellular matrix (ECM). Expression of endostatin, a cleaved fragment of type XVIII collagen, increases in the heart tissue of an experimental myocardial infarction model. In the present study, we examined the effect of endostatin on the function of myofibroblasts derived from an infarcted area. The myocardial infarction model was created by ligating the left anterior descending artery in rats. Two weeks after the operation, α-smooth muscle actin (α-SMA)-positive myofibroblasts were isolated from the infarcted area. Endostatin significantly increased the proliferation and migration of myofibroblasts in vitro. On the other hand, endostatin had no effect on the production of type I collagen, a major ECM protein produced by myofibroblasts. Endostatin activated Akt and extracellular signal-regulated kinase (ERK), and the pharmacological inhibition of these signaling pathways suppressed the endostatin-induced proliferation and migration. A knockdown of the COL18A1 gene in the myocardial infarction model rats using small interference RNA (siRNA) worsened the cardiac function concomitant with wall thinning and decreased the α-SMA-positive myofibroblasts and scar formation compared with that of control siRNA-injected rats. In summary, we demonstrated for the first time that endostatin might be an important factor in the healing process after myocardial infarction through the activation of myofibroblasts. Full article
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18 pages, 1713 KiB  
Article
Chronic Blockade of Brain Endothelin Receptor Type-A (ETA) Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats
by Luis R. Cassinotti, María J. Guil, Mercedes I. Schöller, Mónica P. Navarro, Liliana G. Bianciotti and Marcelo S. Vatta
Int. J. Mol. Sci. 2018, 19(3), 660; https://doi.org/10.3390/ijms19030660 - 27 Feb 2018
Cited by 9 | Viewed by 3813
Abstract
Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also [...] Read more.
Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Following brain ET receptor type A (ETA) blockade by BQ610 (selective antagonist), transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH) were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ETA blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein) in the right OB of hypertensive animals. However, ETA blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ETA are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension. Full article
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12 pages, 1611 KiB  
Article
Disruption of Central Antioxidant Property of Nuclear Factor Erythroid 2-Related Factor 2 Worsens Circulatory Homeostasis with Baroreflex Dysfunction in Heart Failure
by Takuya Kishi
Int. J. Mol. Sci. 2018, 19(3), 646; https://doi.org/10.3390/ijms19030646 - 25 Feb 2018
Cited by 4 | Viewed by 3545
Abstract
Heart failure is defined as a disruption of circulatory homeostasis. We have demonstrated that baroreflex dysfunction strikingly disrupts circulatory homeostasis. Moreover, previous many reports have suggested that central excess oxidative stress causes sympathoexcitation in heart failure. However, the central mechanisms of baroreflex dysfunction [...] Read more.
Heart failure is defined as a disruption of circulatory homeostasis. We have demonstrated that baroreflex dysfunction strikingly disrupts circulatory homeostasis. Moreover, previous many reports have suggested that central excess oxidative stress causes sympathoexcitation in heart failure. However, the central mechanisms of baroreflex dysfunction with oxidative stress has not been fully clarified. Our hypothesis was that the impairment of central antioxidant property would worsen circulatory homeostasis with baroreflex dysfunction in heart failure. As the major antioxidant property in the brain, we focused on nuclear factor erythroid 2-related factor 2 (Nrf2; cytoprotective transcription factor). Hemodynamic and baroreflex function in conscious state were assessed by the radio-telemetry system. In the heart failure treated with intracerebroventricular (ICV) infusion of angiotensin II type 1 receptor blocker (ARB), sympathetic activation and brain oxidative stress were significantly lower, and baroreflex sensitivity and volume tolerance were significantly higher than in heart failure treated with vehicle. ICV infusion of Nrf2 activator decreased sympathetic activation and brain oxidative stress, and increased baroreflex sensitivity and volume tolerance to a greater extent than ARB. In conclusion, the disruption of central antioxidant property of Nrf2 worsened circulatory homeostasis with baroreflex dysfunction in heart failure. Full article
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13 pages, 5686 KiB  
Article
Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen
by Martin Lewis, Adrian Szobi, Dirki Balaska, Igor Khaliulin, Adriana Adameova, Elinor Griffiths, Clive H. Orchard and M.-Saadeh Suleiman
Int. J. Mol. Sci. 2018, 19(2), 494; https://doi.org/10.3390/ijms19020494 - 07 Feb 2018
Cited by 3 | Viewed by 3781
Abstract
Consecutive treatment of adult rat heart with isoproterenol and adenosine (Iso/Aden), known to consecutively activate PKA/PKC signaling, is cardioprotective against ischemia and reperfusion (I/R). Whether this is cardioprotective in an immature heart is unknown. Langendorff–perfused hearts from adult and immature (60 and 14 [...] Read more.
Consecutive treatment of adult rat heart with isoproterenol and adenosine (Iso/Aden), known to consecutively activate PKA/PKC signaling, is cardioprotective against ischemia and reperfusion (I/R). Whether this is cardioprotective in an immature heart is unknown. Langendorff–perfused hearts from adult and immature (60 and 14 days old) male Wistar rats were exposed to 30 min ischemia and 120 min reperfusion, with or without prior perfusion with 5 nM Iso for 3 min followed by 30 μM Aden for 5 min. Changes in hemodynamics (developed pressure and coronary flow) and cardiac injury (Lactate Dehydrogenase (LDH) release and infarct size) were measured. Additional hearts were used to measure glycogen content. Iso induced a similar inotropic response in both age groups. Treatment with Iso/Aden resulted in a significant reduction in time to the onset of ischemic contracture in both age groups whilst time to peak contracture was significantly shorter only in immature hearts. Upon reperfusion, the intervention reduced cardiac injury and functional impairment in adults with no protection of immature heart. Immature hearts have significantly less glycogen content compared to adult. This work shows that Iso/Aden perfusion confers protection in an adult heart but not in an immature heart. It is likely that metabolic differences including glycogen content contribute to this difference. Full article
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4190 KiB  
Article
Ketamine, a Clinically Used Anesthetic, Inhibits Vascular Smooth Muscle Cell Proliferation via PP2A-Activated PI3K/Akt/ERK Inhibition
by Yi Chang, Jiun-Yi Li, Thanasekaran Jayakumar, Shou-Huang Hung, Wei-Cheng Lee, Manjunath Manubolu, Joen-Rong Sheu and Ming-Jen Hsu
Int. J. Mol. Sci. 2017, 18(12), 2545; https://doi.org/10.3390/ijms18122545 - 27 Nov 2017
Cited by 12 | Viewed by 4833
Abstract
Abnormal proliferation of vascular smooth muscle cells (VSMCs) gives rise to major pathological processes involved in the development of cardiovascular diseases. The use of anti-proliferative agents for VSMCs offers potential for the treatment of vascular disorders. Intravenous anesthetics are firmly established to have [...] Read more.
Abnormal proliferation of vascular smooth muscle cells (VSMCs) gives rise to major pathological processes involved in the development of cardiovascular diseases. The use of anti-proliferative agents for VSMCs offers potential for the treatment of vascular disorders. Intravenous anesthetics are firmly established to have direct effects on VSMCs, resulting in modulation of blood pressure. Ketamine has been used for many years in the intensive care unit (ICU) for sedation, and has recently been considered for adjunctive therapy. In the present study, we investigated the effects of ketamine on platelet-derived growth factor BB (PDGF-BB)-induced VSMC proliferation and the associated mechanism. Ketamine concentration-dependently inhibited PDGF-BB-induced VSMC proliferation without cytotoxicity, and phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated protein kinase (ERK) inhibitors, LY294002 and PD98059, respectively, have similar inhibitory effects. Ketamine was shown to attenuate PI3K, Akt, and ERK1/2 phosphorylation induced by PDGF-BB. Okadaic acid, a selective protein phosphatase 2A (PP2A) inhibitor, significantly reversed ketamine-mediated PDGF-BB-induced PI3K, Akt, and ERK1/2 phosphorylation; a transfected protein phosphatse 2a (pp2a) siRNA reversed Akt and ERK1/2 phosphorylation; and 3-O-Methyl-sphingomyeline (3-OME), an inhibitor of sphingomyelinase, also significantly reversed ERK1/2 phosphorylation. Moreover, ketamine alone significantly inhibited tyrosine phosphorylation and demethylation of PP2A in a concentration-dependent manner. In addition, the pp2a siRNA potently reversed the ketamine-activated catalytic subunit (PP2A-C) of PP2A. These results provide evidence of an anti-proliferating effect of ketamine in VSMCs, showing activation of PP2A blocks PI3K, Akt, and ERK phosphorylation that subsequently inhibits the proliferation of VSMCs. Thus, ketamine may be considered a potential effective therapeutic agent for reducing atherosclerotic process by blocking the proliferation of VSMCs. Full article
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2042 KiB  
Article
Alteration of Vascular Responsiveness to Uridine Adenosine Tetraphosphate in Aortas Isolated from Male Diabetic Otsuka Long-Evans Tokushima Fatty Rats: The Involvement of Prostanoids
by Takayuki Matsumoto, Shota Kobayashi, Makoto Ando, Maika Iguchi, Keisuke Takayanagi, Mihoka Kojima, Kumiko Taguchi and Tsuneo Kobayashi
Int. J. Mol. Sci. 2017, 18(11), 2378; https://doi.org/10.3390/ijms18112378 - 09 Nov 2017
Cited by 12 | Viewed by 3411
Abstract
We investigated whether responsiveness to dinucleotide uridine adenosine tetraphosphate (Up4A) was altered in aortas from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats compared with those from age-matched control Long-Evans Tokushima Otsuka (LETO) rats at the chronic stage of disease. [...] Read more.
We investigated whether responsiveness to dinucleotide uridine adenosine tetraphosphate (Up4A) was altered in aortas from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats compared with those from age-matched control Long-Evans Tokushima Otsuka (LETO) rats at the chronic stage of disease. In OLETF aortas, we observed the following: (1) Up4A-induced contractions were lower than those in the LETO aortas under basal conditions, (2) slight relaxation occurred due to Up4A, but this was not observed in phenylephrine-precontracted LETO aortas, (3) acetylcholine-induced relaxation was reduced (vs. LETO), and (4) prostanoid release (prostaglandin (PG)F, thromboxane (Tx)A2 metabolite, and PGE2) due to Up4A was decreased (vs. LETO). Endothelial denudation suppressed Up4A-induced contractions in the LETO group, but increased the contractions in the OLETF group. Under nitric oxide synthase (NOS) inhibition, Up4A induced contractions in phenylephrine-precontracted aortas; this effect was greater in the LETO group (vs. the OLETF group). The relaxation response induced by Up4A was unmasked by cyclooxygenase inhibitors, especially in the LETO group, but this effect was abolished by NOS inhibition. These results suggest that the relaxant component of the Up4A-mediated response was masked by prostanoids in the LETO aortas and that the LETO and OLETF rats presented different contributions of the endothelium to the response. Full article
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11118 KiB  
Article
Beneficial Effects of Galectin-3 Blockade in Vascular and Aortic Valve Alterations in an Experimental Pressure Overload Model
by Jaime Ibarrola, Ernesto Martínez-Martínez, J. Rafael Sádaba, Vanessa Arrieta, Amaia García-Peña, Virginia Álvarez, Amaya Fernández-Celis, Alicia Gainza, Patrick Rossignol, Victoria Cachofeiro Ramos and Natalia López-Andrés
Int. J. Mol. Sci. 2017, 18(8), 1664; https://doi.org/10.3390/ijms18081664 - 31 Jul 2017
Cited by 18 | Viewed by 4731
Abstract
Galectin-3 (Gal-3) is involved in cardiovascular fibrosis and aortic valve (AV) calcification. We hypothesized that Gal-3 pharmacological inhibition with modified citrus pectin (MCP) could reduce aortic and AV remodeling in normotensive rats with pressure overload (PO). Six weeks after aortic constriction, vascular Gal-3 [...] Read more.
Galectin-3 (Gal-3) is involved in cardiovascular fibrosis and aortic valve (AV) calcification. We hypothesized that Gal-3 pharmacological inhibition with modified citrus pectin (MCP) could reduce aortic and AV remodeling in normotensive rats with pressure overload (PO). Six weeks after aortic constriction, vascular Gal-3 expression was up-regulated in male Wistar rats. Gal-3 overexpression was accompanied by an increase in the aortic media layer thickness, enhanced total collagen, and augmented expression of fibrotic mediators. Further, vascular inflammatory markers as well as inflammatory cells content were greater in aorta from PO rats. MCP treatment (100 mg/kg/day) prevented the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of PO rats. Gal-3 levels were higher in AVs from PO rats. This paralleled enhanced AV fibrosis, inflammation, as well as greater expression of calcification markers. MCP treatment prevented the increase in Gal-3 as well as fibrosis, inflammation, and calcification in AVs. Overall, Gal-3 is overexpressed in aorta and AVs from PO rats. Gal-3 pharmacological inhibition blocks aortic and AV remodeling in experimental PO. Gal-3 could be a new therapeutic approach to delay the progression and the development of aortic remodeling and AV calcification in PO. Full article
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Review

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23 pages, 2052 KiB  
Review
Within the Brain: The Renin Angiotensin System
by LaDonya Jackson, Wael Eldahshan, Susan C. Fagan and Adviye Ergul
Int. J. Mol. Sci. 2018, 19(3), 876; https://doi.org/10.3390/ijms19030876 - 15 Mar 2018
Cited by 213 | Viewed by 11554
Abstract
For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within [...] Read more.
For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Interestingly, a crosstalk between the RAS and other systems such as cholinergic, dopaminergic and adrenergic systems have been demonstrated. In this review, the preclinical and clinical evidence for the impact of RAS modulators on cognitive impairment of multiple etiologies will be discussed. In addition, the expression and function of different receptor subtypes within the RAS such as: Angiotensin II type I receptor (AT1R), Angiotensin II type II receptor (AT2R), Angiotensin IV receptor (AT4R), Mas receptor (MasR), and Mas-related-G protein-coupled receptor (MrgD), on different cell types within the brain will be presented. We aim to direct the attention of the scientific community to the plethora of evidence on the importance of the RAS on cognition and to the different disease conditions in which these agents can be beneficial. Full article
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20 pages, 2178 KiB  
Review
Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147) in Cardiovascular Disease
by Saskia N. I. Von Ungern-Sternberg, Alma Zernecke and Peter Seizer
Int. J. Mol. Sci. 2018, 19(2), 507; https://doi.org/10.3390/ijms19020507 - 08 Feb 2018
Cited by 45 | Viewed by 7103
Abstract
The receptor EMMPRIN is involved in the development and progression of cardiovascular diseases and in the pathogenesis of myocardial infarction. There are several binding partners of EMMPRIN mediating the effects of EMMPRIN in cardiovascular diseases. EMMPRIN interaction with most binding partners leads to [...] Read more.
The receptor EMMPRIN is involved in the development and progression of cardiovascular diseases and in the pathogenesis of myocardial infarction. There are several binding partners of EMMPRIN mediating the effects of EMMPRIN in cardiovascular diseases. EMMPRIN interaction with most binding partners leads to disease progression by mediating cytokine or chemokine release, the activation of platelets and monocytes, as well as the formation of monocyte-platelet aggregates (MPAs). EMMPRIN is also involved in atherosclerosis by mediating the infiltration of pro-inflammatory cells. There is also evidence that EMMPRIN controls energy metabolism of cells and that EMMPRIN binding partners modulate intracellular glycosylation and trafficking of EMMPRIN towards the cell membrane. In this review, we systematically discuss these multifaceted roles of EMMPRIN and its interaction partners, such as Cyclophilins, in cardiovascular disease. Full article
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15 pages, 3240 KiB  
Review
Overview of the Microenvironment of Vasculature in Vascular Tone Regulation
by Yean Chun Loh, Chu Shan Tan, Yung Sing Ch’ng, Zhao Qin Yeap, Chiew Hoong Ng and Mun Fei Yam
Int. J. Mol. Sci. 2018, 19(1), 120; https://doi.org/10.3390/ijms19010120 - 02 Jan 2018
Cited by 25 | Viewed by 10079
Abstract
Hypertension is asymptomatic and a well-known “silent killer”, which can cause various concomitant diseases in human population after years of adherence. Although there are varieties of synthetic antihypertensive drugs available in current market, their relatively low efficacies and major application in only single [...] Read more.
Hypertension is asymptomatic and a well-known “silent killer”, which can cause various concomitant diseases in human population after years of adherence. Although there are varieties of synthetic antihypertensive drugs available in current market, their relatively low efficacies and major application in only single drug therapy, as well as the undesired chronic adverse effects associated, has drawn the attention of worldwide scientists. According to the trend of antihypertensive drug evolution, the antihypertensive drugs used as primary treatment often change from time-to-time with the purpose of achieving the targeted blood pressure range. One of the major concerns that need to be accounted for here is that the signaling mechanism pathways involved in the vasculature during the vascular tone regulation should be clearly understood during the pharmacological research of antihypertensive drugs, either in vitro or in vivo. There are plenty of articles that discussed the signaling mechanism pathways mediated in vascular tone in isolated fragments instead of a whole comprehensive image. Therefore, the present review aims to summarize previous published vasculature-related studies and provide an overall depiction of each pathway including endothelium-derived relaxing factors, G-protein-coupled, enzyme-linked, and channel-linked receptors that occurred in the microenvironment of vasculature with a full schematic diagram on the ways their signals interact. Furthermore, the crucial vasodilative receptors that should be included in the mechanisms of actions study on vasodilatory effects of test compounds were suggested in the present review as well. Full article
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