Delayed changes in the transcriptomic profile of cerebral arteries in a rat model of subarachnoid hemorrhage.

Aneurismal subarachnoid hemorrhage (aSAH) is a neurovascular disease characterized by blood released into the subarachnoid space due to rupture of the cerebral arteries. After the onset of bleeding, secondary associated vasospasm (VSP) remains a dramatic side effect that causes severe comorbidities. We analyzed alterations in the expression profiles of arteries from a rat model of SAH using microarray and bioinformatics approaches.

HDL anti-inflammatory function is impaired and associated with high SAA1 and low APOA4 levels in aneurysmal subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease with high morbidity and mortality rates. Within 24 hours after aSAH, monocytes are recruited and enter the subarachnoid space, where they mature into macrophages, increasing the inflammatory response and contributing, along with other factors, to delayed neurological dysfunction and poor outcomes. High-density lipoproteins (HDL) are lipid-protein complexes that exert anti-inflammatory effects but under pathological conditions undergo structural alterations that have been associated with loss of functionality.

Acute oxygen sensing by vascular smooth muscle cells.

An adequate supply of oxygen (O) is essential for most life forms on earth, making the delivery of appropriate levels of O to tissues a fundamental physiological challenge. When O levels in the alveoli and/or blood are low, compensatory adaptive reflexes are produced that increase the uptake of O and its distribution to tissues within a few seconds. This paper analyzes the most important acute vasomotor responses to lack of O (hypoxia): hypoxic pulmonary vasoconstriction (HPV) and hypoxic vasodilation (HVD).

Decrease in acute periprosthetic joint infections incidence with vancomycin-loaded calcium sulfate beads in patients with non-modifiable risk factors. A randomized clinical trial.

Objectives: The influence of local antibiotic therapy in orthopedic surgery remains unclear. In this trial, we evaluated the incidence of periprosthetic joint infections (PJI), after local or intravenous (IV) antibiotic prophylaxis. The aim of this intervention was to compare the PJI incidence in a population with non-modifiable risk factors after local prophylaxis with vancomycin-loaded calcium sulfate beads versus a control group.

The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function.

Background: In chronic kidney disease (CKD) patients, increased levels of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality. The relationship between FGF23 and heart hypertrophy has been documented, however, it is not known whether FGF23 has an effect on vasculature. Vascular smooth muscle cells VSMCs may exhibit different phenotypes; our hypothesis is that FGF23 favours a switch from a contractile to synthetic phenotype that may cause vascular dysfunction.

Membrane Cargo Density-Dependent Interaction between Protein and Lipid Domains on the Giant Unilamellar Vesicles.

Protein cargos anchored on the lipid membrane can be segregated by fluidic domain phase separation. Lipid membranes at certain compositions may separate into lipid domains to segregate cargos, and protein cargos themselves may be involved in protein condensate domain formation with multivalent binding proteins to segregate cargos. Recent studies suggest that these two driving forces of phase separation closely interact on the lipid membranes to promote codomain formation.

Intelligent fluorescence image analysis of giant unilamellar vesicles using convolutional neural network.

Background: Fluorescence image analysis in biochemical science often involves the complex tasks of identifying samples for analysis and calculating the desired information from the intensity traces. Analyzing giant unilamellar vesicles (GUVs) is one of these tasks. Researchers need to identify many vesicles to statistically analyze the degree of molecular interaction or state of molecular organization on the membranes.

Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage.

Toll-like receptors (TLRs) or pattern recognition receptors respond to pathogen-associated molecular patterns (PAMPs) or internal damage-associated molecular patterns (DAMPs). TLRs are integral membrane proteins with both extracellular leucine-rich and cytoplasmic domains that initiate downstream signaling through kinases by activating transcription factors like AP-1 and NF-κB, which lead to the release of various inflammatory cytokines and immune modulators. In the central nervous system, different TLRs are expressed mainly in microglia and astroglial cells, although some TLRs are also expressed in oligodendroglia and neurons.

A targeted polypeptide-based nanoconjugate as a nanotherapeutic for alcohol-induced neuroinflammation.

Alcohol abuse induces the expression of inflammatory mediators by activating the immune receptors to trigger neuroinflammation and brain damage; however, therapies that reduce neuroimmune system activation may protect against alcohol's damaging effects. Curcuminoids possess anti-inflammatory properties but suffer from low bioavailability; therefore, we designed a new receptor-targeted biodegradable star-shaped crosslinked polypeptide polymer that bears propargylamine moieties and bisdemethoxycurcumin (StClPr-BDMC-ANG) as an enhanced anti-inflammatory therapeutic that penetrates the blood-brain-barrier and ameliorates alcohol-induced neuroinflammation. StClPr-BDMC-ANG administration maintains the viability of primary glia and inhibits the ethanol-induced upregulation of crucial inflammatory mediators in the prefrontal and medial cortex in a mouse model of chronic ethanol consumption.

PKCα-Mediated Downregulation of RhoA Activity in Depolarized Vascular Smooth Muscle: Synergistic Vasorelaxant Effect of PKCα and ROCK Inhibition.

Background/aims: Protein kinase C (PKC)- and RhoA/Rho-associated kinase (ROCK) play important roles in arterial sustained contraction. Although depolarization-elicited RhoA/ROCK activation is accepted, the role of PKC in depolarized vascular smooth muscle cells (VSMCs) is a subject of controversy. Our aim was to study the role of PKC in arterial contraction and its interaction with RhoA/ROCK.

Contribution of L-type Ca channel-sarcoplasmic reticulum coupling to depolarization-induced arterial contraction in spontaneously hypertensive rats.

Evidence has shown that vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs) are depolarized and that the expression of L-type Ca channels (LTCCs) and the sarcoplasmic reticulum (SR) Ca buffering system are upregulated. Arterial rings exposed to high K solutions develop a contraction with two components, namely, an initial or phasic component and a sustained or tonic component. Because LTCCs and SR have different functions in the phasic and tonic components of depolarization-induced contraction, this study investigated the role of LTCC-SR coupling in depolarized arterial rings of SHRs.

Relation of RhoA in Peripheral Blood Mononuclear Cells With Severity of Aneurysmal Subarachnoid Hemorrhage and Vasospasm.

Background And Purpose: Rho-kinase, an effector of RhoA, is associated with various cardiovascular diseases in circulating blood cells. However, the role of RhoA/Rho-kinase in peripheral blood mononuclear cells from patients with spontaneous aneurysmal subarachnoid hemorrhage (aSAH) has not yet been studied in relation to the severity of this disease. Therefore, we analyzed the expression and activity of RhoA as a possible biomarker in aSAH.

Regulation of RhoA/ROCK and sustained arterial contraction by low cytosolic Ca levels during prolonged depolarization of arterial smooth muscle.

The role of L-type Ca channels (LTCCs) and RhoA/Rho kinase (ROCK) on depolarization-induced sustained arterial contraction lasting several minutes is already known. However, in vivo, vascular smooth muscle cells can be depolarized for longer periods, inducing substantial inactivation of LTCCs and markedly reducing Ca influx into the myocytes. We have examined, in femoral arterial rings, the role of LTCCs and RhoA/ROCK during long-lasting depolarization.

Role of L-type Ca(2+) channels, sarcoplasmic reticulum and Rho kinase in rat basilar artery contractile properties in a new model of subarachnoid hemorrhage.

We have previously described that L-type Ca(2+) channels' (LTCCs) activation and metabotropic Ca(2+) release from the sarcoplasmic reticulum (SR) regulate RhoA/Rho kinase (ROCK) activity and sustained arterial contraction. We have investigated whether this signaling pathway can be altered in a new experimental model of subarachnoid hemorrhage (SAH). For this purpose, arterial reactivity was evaluated on days 1 to 5 after surgery.

Low-dose combination of Rho kinase and L-type Ca(2+) channel antagonists for selective inhibition of depolarization-induced sustained arterial contraction.

L-type Ca(2+) channels (LTCCs) are involved in the maintenance of tonic arterial contractions and regulate the RhoA/Rho-associated kinase (ROCK) sensitization cascade. We have tested effects of individual and combined low concentrations of LTCCs and ROCK inhibitors to produce arterial relaxation without the adverse side effects of LTCCs antagonists. We have also studied whether this pharmacological strategy alters Ca(2+)-dependent electrical properties of isolated arterial and cardiac myocytes as well as cardiac contractility.

Contractile responses to rat urotensin II in resting and depolarized basilar arteries.

The effects of human urotensin II (hUII) on the vascular tone of different animal species has been studied extensively. However, little has been reported on the vasoactive effects of rat urotensin (rUII) in murine models. The aim of the present study was to investigate the effects of rUII on vasoreactivity in rat basilar arteries.

A new metabotropic role for L-type Ca(2+) channels in vascular smooth muscle contraction.

Vascular smooth muscle cells (VSMCs) contraction can be evoked by the rise of cytosolic [Ca(2+)] owing to transmembrane Ca(2+) influx or sarcoplasmic reticulum (SR) Ca(2+) release. Although the classical ionotropic role of voltagedependent (L-type) Ca(2+) channels (VGCCs) is known, we review here data suggesting a new metabotropic function of VGCCs in vascular smooth muscle cells. VGCCs can trigger Ca(2+) release from the SR in the absence of extracellular Ca2+.

Tonic arterial contraction mediated by L-type Ca2+ channels requires sustained Ca2+ influx, G protein-associated Ca2+ release, and RhoA/ROCK activation.

KCl-evoked sustained contraction requires L-type Ca(2+) channel activation, metabotropic Ca(2+) release from the sarcoplasmic reticulum (mechanism denoted calcium channel-induced Ca(2+) release) and RhoA/Rho associated kinase activation. Although high K(+) solutions are used to depolarize myocytes, these solutions can stimulate other signaling pathways such as those triggered by the activation of muscarinic and purinergic receptors. The present study examines the functional role of calcium channel-induced Ca(2+) release under pharmacological activation of L-type Ca(2+) channel without significant membrane depolarization.

Metabotropic regulation of RhoA/Rho-associated kinase by L-type Ca2+ channels.

Sustained vascular smooth muscle contraction can be mediated by several mechanisms, including the influx of extracellular Ca(2+) through L-type voltage-gated Ca(2+) channels (LTCCs) and by RhoA/Rho-associated kinase (ROCK)-dependent Ca(2+) sensitization of the contractile machinery. Conformational changes in the LTCC following depolarization can also trigger an ion-independent metabotropic pathway that involves G protein/phospholipase C activation, giving rise to inositol 1,4,5-trisphosphate synthesis and subsequent Ca(2+) release from the sarcoplasmic reticulum (SR) (calcium channel-induced Ca(2+) release or calcium channel-induced calcium release [CCICR]). In this review, we summarize recent data suggesting that LTCC activation and subsequent metabotropic Ca(2+) release from the SR participate in depolarization-evoked RhoA/ROCK activity and sustained arterial contraction.

Tungstate activates BK channels in a β subunit- and Mg2+-dependent manner: relevance for arterial vasodilatation.

Aims: Tungstate reduces blood pressure in experimental animal models of both hypertension and metabolic syndrome, although the underlying mechanisms are not fully understood. Given that the large-conductance voltage- and Ca(2+)-dependent K(+) (BK) channel is a key element in the control of arterial tone, our aim was to evaluate whether BK channel modulation by tungstate can contribute to its antihypertensive effect.

Methods And Results: Patch-clamp studies of heterologously expressed human BK channels (α + β(1-4) subunits) revealed that cytosolic tungstate (1 mM) induced a significant left shift (∼20 mV) in the voltage-dependent activation curve only in BK channels containing αβ(1) or αβ(4) subunits, but reduced the amplitude of K(+) currents through all BK channels tested.

Metabotropic regulation of RhoA/Rho-associated kinase by L-type Ca2+ channels: new mechanism for depolarization-evoked mammalian arterial contraction.

Background: Sustained vascular smooth muscle contraction is mediated by extracellular Ca(2+) influx through L-type voltage-gated Ca(2+) channels (VGCC) and RhoA/Rho-associated kinase (ROCK)-dependent Ca(2+) sensitization of the contractile machinery. VGCC activation can also trigger an ion-independent metabotropic pathway that involves G-protein/phospholipase C activation, inositol 1,4,5-trisphosphate synthesis, and Ca(2+) release from the sarcoplasmic reticulum (calcium channel-induced Ca(2+) release). We have studied the functional role of calcium channel-induced Ca(2+) release and the inter-relations between Ca(2+) channel and RhoA/ROCK activation.