Extrahelical Binding Site for a 1H-Imidazo[4,5-c]quinolin-4-amine A3 Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7.

This study describes the localization and computational prediction of a binding site for the A3 adenosine receptor (A3AR) positive allosteric modulator 2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1H-imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y2847.55 in TMD7 and Y2938.54 in H8 and by π-NH bonding between Y2847.55 and the exocyclic amine. The 2-cyclohexyl group is positioned "upward" within a small hydrophobic subpocket created by residues in TMDs 1 and 7, while the 3,4-dichlorophenyl group extends toward the lipid interface. An H-bond between the N-1 amine of the heterocycle and the carbonyl of G291.49 further stabilizes the interaction. Molecular dynamics simulations predicted two metastable intermediates, one resembling a pose determined by molecular docking and a second involving transient interactions with Y2938.54; in simulations, each of these intermediates converges into the final bound state. Structure-activity-relationships for replacement of either of the identified exocyclic or endocyclic amines with heteroatoms lacking H-bond donating ability were consistent with the hypothetical pose. Thus, we characterized an allosteric pocket for 1H-imidazo[4,5-c]quinolin-4-amines that is consistent with data generated by orthogonal methods, which will aid in the rational design of improved A3AR positive allosteric modulators. SIGNIFICANCE STATEMENT: Orthosteric A3AR agonists have advanced in clinical trials for inflammatory conditions, liver diseases, and cancer. Thus, the clinical appeal of selective receptor activation could extend to allosteric enhancers, which would induce site- and time-specific activation in the affected tissue. By identifying the allosteric site for known positive allosteric modulators, structure-based drug discovery modalities can be enabled to enhance the pharmacological properties of the 1H-imidazo[4,5-c]quinolin-4-amine class of A3AR positive allosteric modulators.

Soluble epoxide hydrolase inhibition improves cognitive function and parenchymal artery dilation in a hypertensive model of chronic cerebral hypoperfusion.

OBJECTIVE: Parenchymal arterioles (PAs) regulate perfusion of the cerebral microcirculation, and impaired PA endothelium-dependent dilation occurs in dementia models mimicking chronic cerebral hypoperfusion (CCH). Epoxyeicosatrienoic acids (EETs) are vasodilators; their actions are potentiated by soluble epoxide hydrolase (sEH) inhibition. We hypothesized that chronic sEH inhibition with trifluoromethoxyphenyl-3 (1-propionylpiperidin-4-yl) urea (TPPU) would prevent cognitive dysfunction and improve PA dilation in a hypertensive CCH model. METHODS: Bilateral carotid artery stenosis (BCAS) was used to induce CCH in twenty-week-old male stroke-prone spontaneously hypertensive rats (SHSRP) that were treated with vehicle or TPPU for 8 weeks. Cognitive function was assessed by novel object recognition. PA dilation and structure were assessed by pressure myography, and mRNA expression in brain tissue was assessed by qRT-PCR. RESULTS: TPPU did not enhance resting cerebral perfusion, but prevented CCH-induced memory deficits. TPPU improved PA endothelium-dependent dilation but reduced the sensitivity of PAs to a nitric oxide donor. TPPU treatment had no effect on PA structure or biomechanical properties. TPPU treatment increased brain mRNA expression of brain derived neurotrophic factor, doublecortin, tumor necrosis factor-alpha, sEH, and superoxide dismutase 3, CONCLUSIONS: These data suggest that sEH inhibitors may be viable treatments for cognitive impairments associated with hypertension and CCH.

Rs10230207 genotype confers changes in HDAC9 and TWIST1, but not FERD3L in lymphoblasts from patients with intracranial aneurysm.

Intracranial aneurysms (IA) are weakened outpouchings of the arterial wall in the cerebrovasculature. Rupture of an IA often leads to devastating consequences. The early identification of IA patients is crucial for management of their condition. A genetic variant at rs10230207, located nearby the HDAC9, TWIST1, and FERD3L genes, is associated with IA. HDAC9 is a class IIa histone deacetylase that mediates vascular smooth muscle cell dysfunction. TWIST1 is a mechanosensitive transcription factor and its expression is reduced in unstable carotid atherosclerotic plaques. In this study, the expression of the HDAC9, TWIST1, and FERD3L genes was characterized and associated with the presence of the rs10230207 genetic variant. Allelic discrimination and gene expression analysis were performed using lymphoblasts from 85 population controls and 109 IA patients. Subjects that were heterozygous (GT) within rs10230207 were 4.32 times more likely to have an IA than those that were homozygous for the reference allele (GG; 95%CI 1.23 to 14.16). Subjects that were homozygous (TT) were 8.27 times more likely to have an IA than those that were GG (95%CI 2.45 to 27.85). While the presence of the risk allele was not associated with changes in FERD3L gene expression, the risk allele was associated with increased HDAC9 and decrease in TWIST1 mRNA expression. The significant inverse correlation between HDAC9 and TWIST1 gene expression suggests that changes in the expression of both of genes may contribute to the formation of IAs.

Carotid artery stenosis in hypertensive rats impairs dilatory pathways in parenchymal arterioles.

Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium-dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits.

Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension.

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16-18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg-1·min-1) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg-1·day-1) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5-14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10-9-10-5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10-5 mol/l) and indomethacin (10-4 mol/l). We used GSK2193874 (10-7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10-9-10-5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension. NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.

Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles.

Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.

Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs).

A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs) (2,4-disubstituted-1H-imidazo[4,5-c]quinolin-4-amines) allosterically increase the Emax of A3AR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse A3ARs. The chain length, functionality, and attachment position were varied to modulate A3AR PAM activity. For example, 26 (MRS8247, p-alkyne-linked 8 methylenes) and homologues increased agonist Cl-IB-MECA's Emax and potency ([35S]GTPγS binding). The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved A3AR PAM activity through rational design based on an extrahelical, lipidic binding site.

Optimal Use of Advanced Practice Providers at an Academic Medical Center: A First-Year Retrospective Review.

Background Physician assistants/associates (PAs) and nurse practitioners (NPs), together known as advanced practice providers (APPs), practice with a high degree of clinical autonomy and professional respect, and play a critical role in team-based care. Aligning APP care delivery models to promote top-of-license practice is essential to improving ambulatory capacity and bottom-line expectations at academic medical centers (AMCs) in the 21st century and beyond. This administrative quality improvement study assesses the downstream impact of restructuring our APP care models to promote independent practice sessions. Methods Our AMC formed an APP oversight committee in April 2021 to optimize the ambulatory care model, realign APP funds flow, and set performance standards to which PAs and NPs are being held accountable. We conducted a one-year retrospective review of internal data from July 2021 to June 30, 2022. Certified registered nurse anesthetists (CRNAs) were excluded from this analysis. Results  APP productivity year-over-year (YOY) aggregate data across all School of Medicine (SOM) departments, demonstrated a 53% increase in work relative value units (wRVUs), 84% increase in payments, and 79% increase in charges from the prior fiscal year (July to June). Regarding APP ambulatory clinical effort (YOY), there was a 45% increase in the number of APP completed visits (92% return patient visits, 8% new visits). An increase in APP productivity did not adversely impact patient satisfaction, physician-generated wRVUs, or delay programmatic expansion efforts. Lastly, in a recent engagement survey, the majority of PA and NP respondents (78%) reported working either "most of the time" or "always" at the top-of-license. Conclusion This quality improvement study demonstrates that enhancement of PA and NP utilization through top-of-license initiatives can be achieved without jeopardizing physician wRVUs or performance. While we acknowledge, there are differences between healthcare institutions in terms of care delivery and compensation models, organizational culture, and distribution of clinical resources, there remains an opportunity among hospitals and health systems to optimize this critical and essential APP workforce.

First Potent Macrocyclic A3 Adenosine Receptor Agonists Reveal G-Protein and ß-Arrestin2 Signaling Preferences.

(N)-Methanocarba adenosine derivatives (A3 adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at N6 and C2 positions with terminal alkenes for ring closure. The resulting macrocycles of 17-20 atoms retained affinity, indicating a spatially proximal orientation of these receptor-bound chains, consistent with molecular modeling of 12. C2-Arylethynyl-linked macrocycle 19 was more A3AR-selective than 2-ether-linked macrocycle 12 (both 5'-methylamides, human (h) A3AR affinities (Ki): 22.1 and 25.8 nM, respectively), with lower mouse A3AR affinities. Functional hA3AR comparison of two sets of open/closed analogues in ß-arrestin2 and Gi/o protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1. The potencies of 1 at all three Gαi isoforms were slightly less than its hA3AR binding affinity (Ki: 1.4 nM), while the Gαi1 and Gαi2 potencies of macrocycle 12 were roughly an order of magnitude higher than its radioligand binding affinity. Gαi2-coupling was enhanced in macrocycle 12 (EC50 2.56 nM, ∼40% greater maximal efficacy than 1). Di-O-allyl precursor 18 cyclized to form 19, increasing the Gαi1 potency by 7.5-fold. The macrocycles 12 and 19 and their open precursors 11 and 18 potently stimulated ß-arrestin2 recruitment, with EC50 values (nM) of 5.17, 4.36, 1.30, and 4.35, respectively, and with nearly 50% greater efficacy compared to 1. This example of macrocyclization altering the coupling pathways of small-molecule (nonpeptide) GPCR agonists is the first for potent and selective macrocyclic AR agonists. These initial macrocyclic derivatives can serve as a guide for the future design of macrocyclic AR agonists displaying unanticipated pharmacology.

T follicular helper cells in IgE-mediated pathologies.

T follicular helper (Tfh) cells help orchestrate optimal humoral immunity by helping B cells to produce affinity-matured, class-switched antibodies in germinal centers. Recent studies have unveiled the complexity and heterogeneity in Tfh cell populations, particularly with respect to their cytokine production. These distinct Tfh cell subsets help tune the class, magnitude and quality of the immunoglobulins produced by B cells, thus shaping the course of humoral responses. The Tfh cell-B cell axis-dependent antibody production is mostly beneficial, but at times can go awry and result in the generation of pathologic antibodies that can harm the host. While IgE class of antibodies are infamous for their detrimental role in allergic diseases, emerging evidence is indicative of their pathologic roles in other dysregulated immune states. Here, we discuss the role of Tfh cell subsets in the regulation of pathologic IgE production in allergies and other immunopathologic conditions.

Acquisition of novel word meaning via cross situational word learning: An event-related potential study.

Cross-situational statistical word learning (CSWL) refers to the process whereby participants learn new words by tracking ambiguous word-object co-occurrences across time. This study used event-related potentials to explore the acquisition of novel word meanings via CSWL in healthy adults. After learning to associate novel auditory words (e.g., 'ket') with familiar objects (e.g., sword), participants performed a semantic judgement task where the learned novel words were paired with a familiar word belonging to either the same (e.g., dagger) or a different (e.g., harp) semantic category. As a comparison, the task also included word pairs comprising two familiar words. The analyses revealed that the unrelated novel word pairs elicited a similar N400 to that of the unrelated familiar word pairs, but with a different hemispheric distribution (left hemisphere for novel words, right hemisphere for familiar words). These findings demonstrate rapid meaning acquisition via CSWL, which is reflected at a neurophysiological level.

Mineralocorticoid receptor antagonism improves transient receptor potential vanilloid 4-dependent dilation of cerebral parenchymal arterioles and cognition in a genetic model of hypertension.

OBJECTIVE: In a model of secondary hypertension, mineralocorticoid receptor (MR) antagonism during the development of hypertension prevents the impairment of transient receptor potential vanilloid 4 (TRPV4) activation in parenchymal arterioles (PAs) and cognitive impairment. However, it is unknown whether MR antagonism can improve these impairments when treatment begins after the onset of essential hypertension. We tested the hypothesis that MR activation in stroke-prone spontaneously hypertensive rats (SHRSP) leads to impaired TRPV4-mediated dilation in PAs that is associated with cognitive dysfunction and neuroinflammation. METHODS: 20-22-week-old male SHRSP ±â€Šeplerenone (EPL; 100 mg/kg daily for 4 weeks) were compared to normotensive Sprague-Dawley (SD) rats. Pressure myography was used to assess PA function. Cognition was tested using Y-maze. Neuroinflammation was assessed using immunofluorescence and qRT-PCR. RESULTS: Carbachol-mediated endothelium-dependent dilation was impaired in SHRSP, and MR antagonism improved this without affecting myogenic tone. Dilation to TRPV4 agonist GSK1016790A was impaired in SHRSP, and ELP treatment restored this. Intermediate conductance potassium channel (IKCa)/small conductance potassium channel (SKCa)-mediated dilation was impaired by hypertension and unaffected by EPL treatment. TRPV4 and IKCa/SKCa channel mRNA expression were reduced in PAs from hypertensive rats, and EPL did not improve this. Impairments in PA dilation in SHRSP were associated with cognitive decline, microglial activation, reactive astrogliosis, and neuroinflammation; cognitive and inflammatory changes were improved with MR blockade. CONCLUSIONS: These data advance our understanding of the effects of hypertension on cerebral arterioles using a clinically relevant model and treatment paradigm. Our studies suggest TRPV4 and the MR are potential therapeutic targets to improve cerebrovascular function and cognition during hypertension.

Structure-Activity Studies of 1H-Imidazo[4,5-c]quinolin-4-amine Derivatives as A3 Adenosine Receptor Positive Allosteric Modulators.

We previously reported 1H-imidazo[4,5-c]quinolin-4-amines as A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs). A3AR agonists, but not PAMs, are in clinical trials for inflammatory diseases and liver conditions. We synthesized new analogues to distinguish 2-cyclopropyl antagonist 17 (orthosteric interaction demonstrated by binding and predicted computationally) from PAMs (derivatives with large 2-alkyl/cycloalkyl/bicycloalkyl groups). We predicted PAM binding at a hydrophobic site on the A3AR cytosolic interface. Although having low Caco-2 permeability and high plasma protein binding, hydrophobic 2-cyclohept-4-enyl-N-3,4-dichlorophenyl, MRS7788 18, and 2-heptan-4-yl-N-4-iodophenyl, MRS8054 39, derivatives were orally bioavailable in rat. 2-Heptan-4-yl-N-3,4-dichlorophenyl 14 and 2-cyclononyl-N-3,4-dichlorophenyl 20 derivatives and 39 greatly enhanced Cl-IB-MECA-stimulated [35S]GTPγS binding Emax, with only 12b trending toward decreasing the agonist EC50. A feasible route for radio-iodination at the p-position of a 4-phenylamino substituent suggests a potential radioligand for allosteric site binding. Herein, we advanced an allosteric approach to developing A3AR-activating drugs that are potentially event- and site-specific in action.

Characterization of Dual-Acting A3 Adenosine Receptor Positive Allosteric Modulators That Preferentially Enhance Adenosine-Induced Gαi3 and GαoA Isoprotein Activation.

The A3 adenosine receptor (A3AR) is a promising therapeutic target for inflammatory diseases, cancer, and chronic neuropathic pain, with agonists already in advanced clinical trials. Here we report an in-depth comparison of the pharmacological properties and structure-activity relationships of existing and expanded compound libraries of 2-substituted 1H-imidazo[4,5-c]quinolin-4-amine and 4-amino-substituted quinoline derivatives that function as A3AR positive allosteric modulators (PAMs). We also show that our lead compound from each series enhances adenosine-induced A3AR signaling preferentially toward activation of Gαi3 and GαoA isoproteins, which are coexpressed with the A3AR in immune cells and spinal cord neurons. Finally, utilizing an extracellular/intracellular chimeric A3AR approach composed of sequences from a responding (human) and a nonresponding (mouse) species, we provide evidence in support of the idea that the imidazoquinolin-4-amine class of PAMs variably interacts dually with the orthosteric ligand binding site as well as with a separate allosteric site located within the inner/intracellular regions of the receptor. This study has advanced both structural and pharmacological understanding of these two classes of A3AR PAMs, which includes leads for future pharmaceutical development.

Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A3 Adenosine Receptors: Affinity Enhancement by N6-(2-Phenylethyl) Substitution.

Dopamine-derived N6-substituents, compared to N6-(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A3 adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, Ki = 10.9/17.8 nM, at human/mouse A3AR). 15 was a partial agonist in vitro (hA3AR, cAMP inhibition, 31% Emax; mA3AR, [35S]GTP-γ-S binding, 16% Emax) and in vivo and also antagonized hA3AR in vitro. Distal H-bonding substitutions of the N6-(2-phenylethyl) moiety particularly enhanced mA3AR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mA3AR and hA3AR homology models. These hybrid models were based on an inactive antagonist-bound hA1AR structure for the upper part of TM2 and an agonist-bound hA2AAR structure for the remaining TM portions. These species-independent A3AR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the A3AR, a drug target of growing interest.

Nonsteroidal Anti-Inflammatory Drugs: A Potential Pharmacological Treatment for Intracranial Aneurysm.

BACKGROUND: Saccular intracranial aneurysms (IAs) are outpouchings of the vessel wall of intracranial arteries. Rupture of IAs results in subarachnoid hemorrhage which is associated with high morbidity and mortality. Surgical interventions, such as clipping and coiling, have associated risks. Currently, there are no proven pharmacological treatments to prevent the growth or rupture of IAs. Infiltration of proinflammatory cytokines in response to increased wall sheer stress is a hallmark of IA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are being investigated as potential therapeutic agents for reduction in growth and/or prevention of IA through inhibition of inflammatory pathways. SUMMARY: This review will discuss the role of NSAIDs in attenuating the inflammation that drives IA progression and rupture. There are two main subtypes of NSAIDs, nonselective COX and selective COX-2 inhibitors, both of which have merit in treating IA. Evidence will be presented which shows that NSAIDs inhibit several key inflammatory mediators involved in IA progression including nuclear factor-κB, tumor necrosis factor-α, and matrix metalloproteinases. In addition, the role of NSAIDs in limiting inflammatory cell adhesion to endothelial cells and attenuating endothelial cell senescence will be discussed. Key Messages: There is an abundance of basic science and preclinical data that support NSAIDs as a promising treatment for IA. Additionally, a combination treatment strategy of low-dose aspirin given concomitantly with a selective COX-2 inhibitor may result in a reduced side effect profile compared to aspirin or selective COX-2 inhibitor use alone. Several large clinical trials are currently planned to further investigate the efficacy of NSAIDs as an effective nonsurgical treatment for IAs.

Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia.