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International Journal of Molecular... Apr 2024Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of... (Review)
Review
Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulation, and many cases of severe acute pulmonary embolism have been reported. The demonstrated presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the endothelial cells suggests that direct viral effects, in addition to indirect effects of perivascular inflammation and coagulopathy, may contribute to pulmonary vasculopathy in COVID-19. In this review, we discuss the pathological mechanisms leading to pulmonary vascular damage during acute infection, which appear to be mainly related to thromboembolic events, an impaired coagulation cascade, micro- and macrovascular thrombosis, endotheliitis and hypoxic pulmonary vasoconstriction. As many patients develop post-COVID symptoms, including dyspnea, we also discuss the hypothesis of pulmonary vascular damage and pulmonary hypertension as a sequela of the infection, which may be involved in the pathophysiology of long COVID.
Topics: Humans; COVID-19; SARS-CoV-2; Lung; Pulmonary Embolism; Hypertension, Pulmonary; Post-Acute COVID-19 Syndrome; Thrombosis
PubMed: 38732160
DOI: 10.3390/ijms25094941 -
Cells May 2024Norbormide (NRB) is a -selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to... (Review)
Review
Norbormide (NRB) is a -selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to non- species. However, due to inconsistent efficacy and the emergence of second-generation anticoagulants, its usage declined, with registration lapsing in 2003. NRBs' lethal action in rats entails irreversible vasoconstriction of peripheral arteries, likely inducing cardiac damage: however, the precise chain of events leading to fatality and the target organs involved remain elusive. This unique contractile effect is exclusive to rat arteries and is induced solely by the endo isomers of NRB, hinting at a specific receptor involvement. Understanding NRB's mechanism of action is crucial for developing species-selective toxicants as alternatives to the broad-spectrum ones currently in use. Recent research efforts have focused on elucidating its cellular mechanisms and sites of action using novel NRB derivatives. The key findings are as follows: NRB selectively opens the rat mitochondrial permeability transition pore, which may be a factor that contributes to its lethal effect; it inhibits rat vascular K channels, which potentially controls its -selective vasoconstricting activity; and it possesses intracellular binding sites in both sensitive and insensitive cells, as revealed by fluorescent derivatives. These studies have led to the development of a prodrug with enhanced pharmacokinetic and toxicological profiles, which is currently undergoing registration as a novel efficacious eco-sustainable -selective toxicant. The NRB-fluorescent derivatives also show promise as non-toxic probes for intracellular organelle labelling. This review documents in more detail these developments and their implications.
Topics: Animals; Rats; Rodenticides; Humans; Vasoconstriction; Mitochondrial Permeability Transition Pore
PubMed: 38727324
DOI: 10.3390/cells13090788 -
Journal of the American Heart... May 2024The vasoconstrictor effects of angiotensin II via type 1 angiotensin II receptors in vascular smooth muscle cells are well established, but the direct effects of...
BACKGROUND
The vasoconstrictor effects of angiotensin II via type 1 angiotensin II receptors in vascular smooth muscle cells are well established, but the direct effects of angiotensin II on vascular endothelial cells (VECs) in vivo and the mechanisms how VECs may mitigate angiotensin II-mediated vasoconstriction are not fully understood. The present study aimed to explore the molecular mechanisms and pathophysiological relevance of the direct actions of angiotensin II on VECs in kidney and brain microvessels in vivo.
METHODS AND RESULTS
Changes in VEC intracellular calcium ([Ca]) and nitric oxide (NO) production were visualized by intravital multiphoton microscopy of cadherin 5-Salsa6f mice or the endothelial uptake of NO-sensitive dye 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, respectively. Kidney fibrosis by unilateral ureteral obstruction and Ready-to-use adeno-associated virus expressing Mouse Renin 1 gene (Ren1-AAV) hypertension were used as disease models. Acute systemic angiotensin II injections triggered >4-fold increases in VEC [Ca] in brain and kidney resistance arterioles and capillaries that were blocked by pretreatment with the type 1 angiotensin II receptor inhibitor losartan, but not by the type 2 angiotensin II receptor inhibitor PD123319. VEC responded to acute angiotensin II by increased NO production as indicated by >1.5-fold increase in 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate fluorescence intensity. In mice with kidney fibrosis or hypertension, the angiotensin II-induced VEC [Ca] and NO responses were significantly reduced, which was associated with more robust vasoconstrictions, VEC shedding, and microthrombi formation.
CONCLUSIONS
The present study directly visualized angiotensin II-induced increases in VEC [Ca] and NO production that serve to counterbalance agonist-induced vasoconstriction and maintain residual organ blood flow. These direct and endothelium-specific angiotensin II effects were blunted in disease conditions and linked to endothelial dysfunction and the development of vascular pathologies.
Topics: Animals; Nitric Oxide; Angiotensin II; Hypertension; Kidney; Calcium; Vasoconstriction; Microvessels; Brain; Mice; Disease Models, Animal; Male; Endothelial Cells; Mice, Inbred C57BL; Calcium Signaling
PubMed: 38726925
DOI: 10.1161/JAHA.123.033998 -
Stem Cells (Dayton, Ohio) May 2024Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right...
Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right heart failure. This study aimed to investigate the therapeutic effects of exosomes from Tibetan umbilical cord mesenchymal stem cells on HPH via the TGF-β1/Smad2/3 pathway, comparing them with exosomes from Han Chinese individuals. An HPH rat model was established in vivo, and a hypoxia-induced injury in the rat pulmonary artery smooth muscle cells (rPASMCs) was simulated in vitro. Exosomes from human umbilical cord mesenchymal stem cells were administered to HPH model rats or added to cultured rPASMCs. The therapeutic effects of Tibetan-mesenchymal stem cell-derived exosomes (Tibetan-MSC-exo) and Han-mesenchymal stem cell-derived exosomes (Han-MSC-exo) on HPH were investigated through immunohistochemistry, Western blotting, EdU, and Transwell assays. The results showed that Tibetan-MSC-exo significantly attenuated pulmonary vascular remodeling and right ventricular hypertrophy in HPH rats compared with Han-MSC-exo. Tibetan-MSC-exo demonstrated better inhibition of hypoxia-induced rPASMCs proliferation and migration. Transcriptome sequencing revealed upregulated genes (Nbl1, Id2, Smad6, and Ltbp1) related to the TGFβ pathway. Nbl1 knockdown enhanced hypoxia-induced rPASMCs proliferation and migration, reversing Tibetan-MSC-exo-induced downregulation of TGFβ1 and p-Smad2/3. Furthermore, TGFβ1 overexpression hindered the therapeutic effects of Tibetan-MSC-exo and Han-MSC-exo on hypoxic injury. These findings suggest that Tibetan-MSC-exo favors HPH treatment better than Han-MSC-exo, possibly through the modulation of the TGFβ1/Smad2/3 pathway via Nbl1.
PubMed: 38717187
DOI: 10.1093/stmcls/sxae032 -
ACS Applied Bio Materials May 2024High-altitude regions, cold deserts, permafrost regions, and the polar region have some of the severest cold conditions on earth and pose immense perils of cold injuries...
Elucidation of the Role of TRPV1, VEGF-A, TXA2, Redox Homeostasis, and Inflammatory Cascades in Protection against Cold Injuries by Herbosomal-Loaded PEG-Poloxamer Topical Formulation.
High-altitude regions, cold deserts, permafrost regions, and the polar region have some of the severest cold conditions on earth and pose immense perils of cold injuries to exposed individuals. Accidental and unintended exposures to severe cold, either unintentionally or due to occupational risks, can greatly increase the risk of serious conditions including hypothermia, trench foot, and cold injuries like frostbite. Cold-induced vasoconstriction and intracellular/intravascular ice crystal formation lead to hypoxic conditions at the cellular level. The condition is exacerbated in individuals having inadequate and proper covering and layering, particularly when large area of the body are exposed to extremely cold environments. There is a paucity of preventive and therapeutic pharmacological modalities that have been explored for managing and treating cold injuries. Given this, an efficient modality that can potentiate the healing of frostbite was investigated by studying various complex pathophysiological changes that occur during severe cold injuries. In the current research, we report the effectiveness and healing properties of a standardized formulation, ., a herbosomal-loaded PEG-poloxamer topical formulation (-HPTF), on frostbite. The intricate mechanistic pathways modulated by the novel formulation have been elucidated by studying the pathophysiological sequelae that occur following severe cold exposures leading to frostbite. The results indicate that -HPTF ameliorates the outcome of frostbite, as it activates positive sensory nerves widely distributed in the epidermis transient receptor potential vanilloid 1 (TRPV1), significantly ( < 0.05) upregulates cytokeratin-14, promotes angiogenesis (VEGF-A), prominently represses the expression of thromboxane formation (TXA2), and significantly ( < 0.05) restores levels of enzymatic (glutathione reductase, superoxide dismutase, and catalase) and nonenzymatic antioxidants (glutathione). Additionally, -HPTF attenuates oxidative stress and the expression of inflammatory proteins PGF-2α, NFκB-p65, TNF-α, IL-6, IL-1β, malondialdehyde (MDA), advanced oxidative protein products (AOPP), and protein carbonylation (PCO). Masson's Trichrome staining showed that -HPTF stimulates cellular proliferation, and increases collagen fiber deposition, which significantly ( < 0.05) promotes the healing of frostbitten tissue, as compared to control. We conclude that protection against severe cold injuries by -HPTF is mediated modulation of pathways involving TRPV1, VEGF-A, TXA2, redox homeostasis, and inflammatory cascades. The study is likely to have widespread implications for the prophylaxis and management of moderate-to-severe frostbite conditions.
Topics: Vascular Endothelial Growth Factor A; TRPV Cation Channels; Animals; Poloxamer; Polyethylene Glycols; Homeostasis; Oxidation-Reduction; Biocompatible Materials; Rats; Materials Testing; Cold Injury; Particle Size; Inflammation; Male; Liposomes; Humans; Administration, Topical; Frostbite
PubMed: 38717017
DOI: 10.1021/acsabm.3c01197 -
Purinergic Signalling May 2024Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This... (Review)
Review
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 Ca levels. The P2X subtype receptors facilitate extracellular Ca influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca 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 A 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 P2Y, P2Y, and P2Y 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.
PubMed: 38713328
DOI: 10.1007/s11302-024-10010-5 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Apr 2024To explore the effects of Rhodiola rosea injection on pulmonary shunt and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels during single lung... (Randomized Controlled Trial)
Randomized Controlled Trial
[Effects of injection on intrapulmonary shunt and blood IL-6 and TNF-α levels during single lung ventilation in patients undergoing radical resection of esophageal cancer].
OBJECTIVE
To explore the effects of Rhodiola rosea injection on pulmonary shunt and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels during single lung ventilation in patients undergoing radical resection of esophageal cancer.
METHODS
Forty-six patients undergoing radical operation for esophageal cancer were randomized equally into control group and Rhodiola rosea injection group. In the Rhodiola group, 10 mL of Rhodiola rosea injection was added into 250 mL of normal saline or 5% glucose solution for slow intravenous infusion, and normal saline of the same volume was used in the control group after the patients entered the operation room. At T, T and T, PaO of the patient was recorded and 2 mL of deep venous blood was collected for determination of serum TNF-α and IL-6 levels. The incidence of postoperative atelectasis of the patients was recorded.
RESULTS
Compared with those in the control group, the patients receiving Rhodiola rosea injection had significantly higher PaO and Qs/Qt at T and T (<0.05) and lower serum IL-6 and TNF-α levels at T (<0.05). No significant difference in the incidence of postoperative atelectasis was observed between the two groups (>0.05).
CONCLUSION
Rhodiola rosea injection before anesthesia induction can reduce intrapulmonary shunt during single lung ventilation, improve oxygenation, reduce serum IL-6 and TNF-α levels, and alleviate intraoperative lung injury in patients undergoing radical resection of esophageal cancer.
Topics: Humans; Esophageal Neoplasms; Tumor Necrosis Factor-alpha; Rhodiola; Interleukin-6; One-Lung Ventilation; Female; Male; Middle Aged
PubMed: 38708504
DOI: 10.12122/j.issn.1673-4254.2024.04.12 -
Molecular Nutrition & Food Research May 2024Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes...
SCOPE
Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear.
METHODS AND RESULTS
Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS.
CONCLUSION
Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.
Topics: Animals; Pregnancy; Female; PPAR gamma; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Prenatal Exposure Delayed Effects; Vasoconstriction; Rats, Sprague-Dawley; Dietary Sucrose; Rats; Renal Artery; Male; Phenylephrine; Maternal Nutritional Physiological Phenomena
PubMed: 38704749
DOI: 10.1002/mnfr.202300871 -
Journal of Stroke and Cerebrovascular... May 2024Females are at higher risk than males for a multitude of cerebrovascular conditions, both common and rare; partially resulting from a complex interplay between differing...
Sex-based difference in selected stroke etiologies: cerebral dural sinus venous thrombosis, reversible cerebral vasoconstriction syndrome, dissection, migraine, pregnancy/puerperium/OC use.
Females are at higher risk than males for a multitude of cerebrovascular conditions, both common and rare; partially resulting from a complex interplay between differing process involving genetics, hormonal influences, common cerebrovascular risk factors among others. Specific topics including cervical artery dissection, cerebral dural sinus venous thrombosis, reversible cerebral vasoconstriction syndrome, migraine, along with these disorders in the setting of pregnancy, puerperium and oral contraceptive utilization. Epidemiology, pathophysiology, presentation, basics of management and outcomes are presented, with sex differences throughout.
PubMed: 38703878
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107753 -
Lasers in Medical Science May 2024Pulsed dye lasers are used effectively in the treatment of psoriasis with long remission time and limited side effects. It is, however, not completely understood which...
Pulsed dye lasers are used effectively in the treatment of psoriasis with long remission time and limited side effects. It is, however, not completely understood which biological processes underlie its favorable outcome. Pulsed dye laser treatment at 585-595 nm targets hemoglobin in the blood, inducing local hyperthermia in surrounding blood vessels and adjacent tissues. While the impact of destructive temperatures on blood vessels has been well studied, the effects of lower temperatures on the function of several cell types within the blood vessel wall and its periphery are not known. The aim of our study is to assess the functionality of isolated blood vessels after exposure to moderate hyperthermia (45 to 60°C) by evaluating the function of endothelial cells, smooth muscle cells, and vascular nerves. We measured blood vessel functionality of rat mesenteric arteries (n=19) by measuring vascular contraction and relaxation before and after heating vessels in a wire myograph. To this end, we elicited vascular contraction by addition of either high potassium solution or the thromboxane analogue U46619 to stimulate smooth muscle cells, and electrical field stimulation (EFS) to stimulate nerves. For measurement of endothelium-dependent relaxation, we used methacholine. Each vessel was exposed to one temperature in the range of 45-60°C for 30 seconds and a relative change in functional response after hyperthermia was determined by comparison with the response per stimulus before heating. Non-linear regression was used to fit our dataset to obtain the temperature needed to reduce blood vessel function by 50% (Half maximal effective temperature, ET50). Our findings demonstrate a substantial decrease in relative functional response for all three cell types following exposure to 55°C-60°C. There was no significant difference between the ET50 values of the different cell types, which was between 55.9°C and 56.9°C (P>0.05). Our data show that blood vessel functionality decreases significantly when exposed to temperatures between 55°C-60°C for 30 seconds. The results show functionality of endothelial cells, smooth muscle cells, and vascular nerves is similarly impaired. These results help to understand the biological effects of hyperthermia and may aid in tailoring laser and light strategies for selective photothermolysis that contribute to disease modification of psoriasis after pulsed dye laser treatment.
Topics: Animals; Rats; Male; Lasers, Dye; Myocytes, Smooth Muscle; Vasodilation; Temperature; Muscle, Smooth, Vascular; Endothelial Cells; Vasoconstriction; Endothelium, Vascular; Rats, Wistar
PubMed: 38703271
DOI: 10.1007/s10103-024-04070-7