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American Journal of Physiology. Cell... Apr 2024Diabetes alters the function of ion channels responsible for regulating arterial smooth muscle membrane potential, resulting in vasoconstriction. Our prior research...
Diabetes alters the function of ion channels responsible for regulating arterial smooth muscle membrane potential, resulting in vasoconstriction. Our prior research demonstrated an elevation of TMEM16A in diabetic arteries. Here, we explored the mechanisms involved in Transmembrane protein 16A ( gene expression. Our data indicate that a Snail-mediated repressor complex regulates arterial gene transcription. Snail expression was reduced in diabetic arteries while TMEM16A expression was upregulated. The promoter contained three canonical E-box sites. Electrophoretic mobility and super shift assays revealed that the -154 nt E-box was the binding site of the Snail repressor complex and binding of the repressor complex decreased in diabetic arteries. High glucose induced a biphasic contractile response in pressurized nondiabetic mouse hindlimb arteries incubated ex vivo. Hindlimb arteries incubated in high glucose also showed decreased phospho-protein kinase D1 and TMEM16A expression. In hindlimb arteries from nondiabetic mice, administration of a bolus dose of glucose activated protein kinase D1 signaling to induce Snail degradation. In both in vivo and ex vivo conditions, Snail expression exhibited an inverse relationship with the expression of protein kinase D1 and TMEM16A. In diabetic mouse arteries, phospho-protein kinase D1 increased while Akt2 and pGSK3β levels declined. These results indicate that in nondiabetic mice, high glucose triggers a transient deactivation of the Snail repressor complex to increase arterial TMEM16A expression independently of insulin signaling. Conversely, insulin resistance activates GSK3β signaling and enhances arterial TMEM16A channel expression. These data have uncovered the Snail-mediated regulation of arterial TMEM16A expression and its dysfunction during diabetes. The calcium-activated chloride channel, TMEM16A, is upregulated in the diabetic vasculature to cause increased vasoconstriction. In this paper, we have uncovered that the gene expression is controlled by a Snail-mediated repressor complex that uncouples with both insulin-dependent and -independent pathways to allow for upregulated arterial protein expression thereby causing vasoconstriction. The paper highlights the effect of short- and long-term glucose-induced dysfunction of an ion channel expression as a causative factor in diabetic vascular disease.
Topics: Animals; Mice; Anoctamin-1; Arteries; Diabetes Mellitus; Insulins; Muscle, Smooth, Vascular; Receptor, Insulin
PubMed: 38581667
DOI: 10.1152/ajpcell.00555.2023 -
Cellular and Molecular Life Sciences :... Apr 2024Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca1.2 calcium channel is one primary pathway for...
Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca1.2 calcium channel is one primary pathway for Ca influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K-induced arterial constriction and Ca1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and Ca1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, Ca1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of Ca1.2 channels in VSMCs and MAs. Notably, GS increases K-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates Ca1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.
Topics: Animals; Rats; Calcium; Calcium Channels, L-Type; Constriction; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Glucose; Hyperglycemia; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats, Sprague-Dawley
PubMed: 38575795
DOI: 10.1007/s00018-024-05198-z -
Scientific Reports Apr 2024Ripasudil-brimonidine fixed-dose combination (K-232) simultaneously targets three different intraocular pressure (IOP) lowering mechanisms, increasing trabecular...
Ripasudil-brimonidine fixed-dose combination (K-232) simultaneously targets three different intraocular pressure (IOP) lowering mechanisms, increasing trabecular meshwork outflow and uveoscleral outflow, and reducing aqueous humor production Vascularly, ripasudil induces transient vasodilation, brimonidine transient vasoconstriction. Investigating effects on IOP, aqueous dynamics, and EVP in mice eyes by microneedle and constant-pressure perfusion methods, and on cytoskeletal and fibrotic proteins changes in HTM cells by a gel contraction assay and immunocytochemistry. Ripasudil, K-232, and brimonidine droplets significantly reduced IOP at 30 min, with K-232 sustaining the effect at 60 min. For EVP, only K-232 exhibited reduced EVP until 60 min after instillation. In vitro, ripasudil inhibited gel contractility and TGFβ2-induced fibrotic changes, whereas brimonidine did not. K-232 significantly lowered IOPs in mice by combining the effects of ripasudil and brimonidine. Brimonidine alone also showed IOP reductions with enhanced outflow facility, and the drug did not interfere with the effects of ripasudil on the trabecular meshwork outflow; K-232 and ripasudil alone both significantly lowered the EVP and enhanced outflow facility, demonstrating that K-232 efficiently reduces IOPs.
Topics: Animals; Mice; Brimonidine Tartrate; Aqueous Humor; Intraocular Pressure; Trabecular Meshwork; Isoquinolines; Sulfonamides
PubMed: 38570526
DOI: 10.1038/s41598-024-58212-6 -
Journal of Cellular and Molecular... Apr 2024The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the... (Review)
Review
The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the age-dependent risk of cardiovascular disease, including endothelial dysfunction, excessive permeability, inflammation, impaired angiogenesis, abnormal vasoconstriction, decreased nitric oxide production and apoptosis. Frailty is a loss of physiological reserve and adaptive capacity with advanced age and is accompanied by a pro-inflammatory and pro-oxidative state that promotes vascular dysfunction and thrombosis. This review summarises the role of the RhoA/Rho kinase signalling pathway in endothelial dysfunction, the acquisition of the pro-thrombotic state and vascular ageing. We also discuss the possible role of RhoA/Rho kinase signalling as a promising therapeutic target for the prevention and treatment of age-related cardiovascular disease.
Topics: Humans; Cardiovascular Diseases; rho-Associated Kinases; Thrombosis; Vascular Diseases; Endothelial Cells
PubMed: 38568071
DOI: 10.1111/jcmm.18153 -
BioRxiv : the Preprint Server For... Mar 2024Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction...
Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.
PubMed: 38559150
DOI: 10.1101/2024.03.10.584280 -
Cureus Feb 2024Gastric ischemia is a relatively rare condition that can lead to severe or life-threatening outcomes. It can be caused by various etiological factors, including vascular...
Gastric ischemia is a relatively rare condition that can lead to severe or life-threatening outcomes. It can be caused by various etiological factors, including vascular occlusion, atherosclerosis, vasculitis, hypovolemic shock, cardiac failure, mesenteric ischemia, splanchnic vasoconstriction, and abdominal compartment syndrome. Furthermore, gastric dilation can be caused by volvulus and acute necrotizing gastritis. This condition may go unnoticed in the setting of intestinal obstruction. In this case report, we describe a 43-year-old female who presented with signs, symptoms, and radiological findings indicative of small bowel obstruction accompanied by a severely dilated stomach. Our aim is to highlight the importance of considering gastric ischemia in patients with small bowel obstruction and to demonstrate the outcomes of a surgical approach in such presentations.
PubMed: 38558711
DOI: 10.7759/cureus.55113 -
Physiological Genomics Jun 2024Short-chain fatty acids (SCFAs) produced by the gut bacteria have been associated with cardiovascular dysfunction in humans and rodents. However, studies exploring...
Short-chain fatty acids (SCFAs) produced by the gut bacteria have been associated with cardiovascular dysfunction in humans and rodents. However, studies exploring effects of SCFAs on cardiovascular parameters in the zebrafish, an increasingly popular model in cardiovascular research, remain limited. Here, we performed fecal bacterial 16S sequencing and gas chromatography/mass spectrometry (GC-MS) to determine the composition and abundance of gut microbiota and SCFAs in adult zebrafish. Following this, the acute effects of major SCFAs on heart rate and vascular tone were measured in anesthetized zebrafish larvae using fecal concentrations of butyrate, acetate, and propionate. Finally, we investigated if coincubation with butyrate may lessen the effects of angiotensin II (ANG II) and phenylephrine (PE) on vascular tone in anesthetized zebrafish larvae. We found that the abundance in , , and phyla in the adult zebrafish resembled those reported in rodents and humans. SCFA levels with highest concentration of acetate (27.43 µM), followed by butyrate (2.19 µM) and propionate (1.65 µM) were observed in the fecal samples of adult zebrafish. Immersion in butyrate and acetate produced a ∼20% decrease in heart rate (HR), respectively, with no observed effects of propionate. Butyrate alone also produced an ∼25% decrease in the cross-sectional width of the dorsal aorta (DA) at 60 min (* < 0.05), suggesting compensatory vasoconstriction, with no effects of either acetate or propionate. In addition, butyrate significantly alleviated the decrease in DA cross-sectional width produced by both ANG II and PE. We demonstrate the potential for zebrafish in investigation of host-microbiota interactions in cardiovascular health. We highlight the presence of a core gut microbiota and demonstrate in vivo short-chain fatty acid production in adult zebrafish. In addition, we show cardio-beneficial vasoactive and chronotropic properties of butyrate, and chronotropic properties of acetate in anesthetized zebrafish larvae.
Topics: Animals; Zebrafish; Gastrointestinal Microbiome; Fatty Acids, Volatile; Larva; Heart Rate; Feces; Butyrates; Angiotensin II; Bacteria; Phenylephrine; Acetates; RNA, Ribosomal, 16S
PubMed: 38557279
DOI: 10.1152/physiolgenomics.00013.2024 -
Cureus Feb 2024Introduction Reversible cerebral vasoconstriction syndrome (RCVS) is most commonly characterized by focal or diffuse severe thunderclap headache with or without focal...
Introduction Reversible cerebral vasoconstriction syndrome (RCVS) is most commonly characterized by focal or diffuse severe thunderclap headache with or without focal neurological deficits and associated transient focal vasoconstriction of the intracerebral arteries lasting up to three months. We present six patients diagnosed as RCVS, with three patients presenting with focal neurological deficits without headache and the remaining three with severe headache alone. Neuroimaging revealed focal subarachnoid bleed with or without segmental intracerebral vasospasm, which resolved over three months. Despite thunderclap headache being the most prevalent symptom associated with RCVS, the absence of this symptom should not preclude the diagnosis, especially in the presence of cortical subarachnoid hemorrhage (SAH) or focal segmental intracerebral arterial narrowing. Methods This case series is a retrospective analysis of all patients diagnosed with RCVS between 2018 and 2022, focusing on clinical symptoms, imaging findings, and management. Results Six patients (three males and three females) were diagnosed with RCVS between 2018 and 2022. Three patients presented with typical symptoms, while the remaining three presented with atypical symptoms. Neuroimaging findings ranged from normal to focal SAH with or without arterial narrowing. Conclusion This case series underscores the diverse clinical presentations of RCVS, emphasizing that while thunderclap headache is the predominant symptom, its absence should not exclude the possibility of RCVS, especially when accompanied by focal neurological deficits or cortical SAH. Neuroimaging played a crucial role in identifying the spectrum of findings. These findings highlight the importance of comprehensive evaluation and consideration of RCVS in patients presenting with neurological symptoms, even in the absence of typical headache features.
PubMed: 38550478
DOI: 10.7759/cureus.55066 -
Acta Clinica Croatica Aug 2023Primary angiitis of the central nervous system (PACNS) is a rare and severe disease confined to the central nervous system, i.e., the brain and spinal cord. The... (Review)
Review
Primary angiitis of the central nervous system (PACNS) is a rare and severe disease confined to the central nervous system, i.e., the brain and spinal cord. The etiology, pathogenesis and immune mechanism of PACNS have not yet been completely elucidated. The diagnosis is challenging; it is based upon constellation of clinical picture, cerebrospinal fluid analysis, imaging methods or tissue biopsy as the gold standard. In differential diagnosis of PACNS, it is necessary to rule out infectious, malignant or systemic inflammatory diseases, as well as reversible cerebral vasoconstriction syndrome. Immunosuppressants are cornerstone therapy for PACNS, although evidence-based strategies for the management are lacking so far. PACNS is an entity with considerable morbidity and mortality. Awareness of this rare and heterogeneous disease is crucial for establishing early diagnosis and treatment initiation.
Topics: Humans; Vasculitis, Central Nervous System; Central Nervous System; Immunosuppressive Agents; Brain; Diagnosis, Differential
PubMed: 38549589
DOI: 10.20471/acc.2023.62.02.14 -
International Journal of Molecular... Mar 2024Onboard oxygen-generating systems (OBOGSs) provide increased inspired oxygen (FO) to mitigate the risk of neurologic injury in high altitude aviators. OBOGSs can deliver...
Onboard oxygen-generating systems (OBOGSs) provide increased inspired oxygen (FO) to mitigate the risk of neurologic injury in high altitude aviators. OBOGSs can deliver highly variable oxygen concentrations oscillating around a predetermined FO set point, even when the aircraft cabin altitude is relatively stable. Steady-state exposure to 100% FO evokes neurovascular vasoconstriction, diminished cerebral perfusion, and altered electroencephalographic activity. Whether non-steady-state FO exposure leads to similar outcomes is unknown. This study characterized the physiologic responses to steady-state and non-steady-state FO during normobaric and hypobaric environmental pressures emulating cockpit pressures within tactical aircraft. The participants received an indwelling radial arterial catheter while exposed to steady-state or non-steady-state FO levels oscillating ± 15% of prescribed set points in a hypobaric chamber. Steady-state exposure to 21% FO during normobaria produced arterial blood gas values within the anticipated ranges. Exposure to non-steady-state FO led to PO levels higher upon cessation of non-steady-state FO than when measured during steady-state exposure. This pattern was consistent across all FO ranges, at each barometric condition. Prefrontal cortical activation during cognitive testing was lower following exposure to non-steady-state FO >50% and <100% during both normobaria and hypobaria of 494 mmHg. The serum analyte levels (IL-6, IP-10, MCP-1, MDC, IL-15, and VEGF-D) increased 48 h following the exposures. We found non-steady-state FO levels >50% reduced prefrontal cortical brain activation during the cognitive challenge, consistent with an evoked pattern of neurovascular constriction and dilation.
Topics: Humans; Oxygen; Cytokines; Blood Gas Analysis; Altitude; Prefrontal Cortex
PubMed: 38542250
DOI: 10.3390/ijms25063279