Artery Constriction Research Articles

Extracranial carotid localized fibromuscular dysplasia: A case report and literature review.

Fibromuscular dysplasia (FMD) is a noninflammatory and nonatherosclerotic arteriopathy that is characterized by irregular cellular proliferation and deformed construction of the arterial wall that causes segmentation, constriction, or aneurysm in the intermediate-sized arteries. The incidence of FMD is 0.42-3.4%, and the unilateral occurrence is even rarer. Herein, we report a rare case of a localized extracranial carotid unilateral FMD associated with recurrent transient ischemic attacks (TIAs) treated by extracranial-intracranial bypass for indirect revascularization. The specific localization of the disease rendered our case unique. We conducted a review of the PubMed Medline database search using the following combined formula: ((FMD [Title/Abstract]) AND ((isolated [Title/Abstract]) OR (localized [Title/Abstract]))) AND Internal carotid artery (ICA) (Title/Abstract). Additional resources were included by screening the reference list of the selected papers. A total of six cases were found, and all accounted for localized FMD affecting the ICA. The age range was between 19 and 52, the male-to-female ratio was (2:4), and all of the cases consisted of unilateral carotid FMD, mainly on the left side with a left-to-right ratio of 5:1. The management and outcome of these cases varied according to the case and associated complications. Extracranial localized FMD of the ICA is a rare subtype of FMD that has little documentation in the literature. In our case, it was a localized extracranial carotid unilateral FMD associated with recurrent TIAs. The appropriate treatment was using the intracranial-extracranial bypass.

Bioheat transfer of Blood Flow on Healthy and Unhealthy Bifurcated Artery: Stenosis

The development and progression of stenosis with a high probability of rupture can be altered by changing the heat distribution in the bifurcated artery. The purpose of this study is to investigate the behavior of blood flow from healthy to unhealthy artery bifurcation under the influence of bioheat transfer. The blood flow is modelled as laminar, two-dimensional, steady, incompressible, and characterised as a Newtonian fluid. The Galerkin weighted residual (GWR) method is utilised to solve the governing equations. The behaviour of the blood flow due to different Reynolds numbers and the severity of stenosis is graphically investigated and discussed. The results reveal that the velocity profiles increase as the degrees of constriction increase. However, a lower Reynolds number enhances the axial velocity in an artery. The blood flow behaves differently from healthy to unhealthy on the bifurcated artery in the presence of an arterial constriction. The behaviour is significantly affected by the rate of heat transfer and the location of stenosis.

Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial.

ObjectiveDual pathway inhibition (DPI) by combining acetylsalicylic acid (ASA) with low-dose rivaroxaban has been shown to reduce cardiovascular events in patients with peripheral arterial disease (PAD) when compared to ASA monotherapy. A potential explanation is that inhibition of factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of cardiovascular events. We hypothesize that the addition of rivaroxaban to ASA in PAD patients leads to improved endothelial function.DesignAn investigator-initiated, multicentre trial investigating the effect of DPI on endothelial function.MethodsPatients, diagnosed with PAD, were enrolled in two cohorts: cohort A (Rutherford I-III) and cohort B (Rutherford IV-VI). Participants received ASA monotherapy for a 4-weeks run-in period, followed by 12 weeks of DPI. Macro- and microvascular endothelial dysfunction were studied by measuring carotid artery reactivity upon sympathetic stimulus and by measuring plasma endothelin-1 concentrations, respectively. All measurements were performed during the use of ASA (baseline) and after 12 weeks of DPI.Results159 PAD patients (111 cohort A, 48 cohort B) were enrolled. Twenty patients discontinued study drugs early. Carotid artery constriction upon sympathetic stimulation at baseline (ASA) and after 12 weeks of DPI was similar in the total group, 22.0 vs. 22.7% (p = 1.000), and in the subgroups (Cohort A 22.6 vs. 23.7%, p = 1.000; cohort B 20.5 vs. 20.5%, p = 1.000), respectively. The mean concentration of plasma endothelin-1 at baseline and after 12 weeks of DPI did not differ, 1.70 ± 0.5 vs. 1.66 ± 0.64 pmol/L (p = 0.440) in the total group, 1.69 ± 0.59 vs. 1.62 ± 0.55 pmol/L in cohort A (p = 0.202), and 1.73 ± 0.53 vs. 1.77 ± 0.82 pmol/L in cohort B (p = 0.682), respectively.ConclusionMacro- and microvascular endothelial dysfunction, as reflected by carotid artery reactivity and plasma endothelin-1 concentrations, are not influenced in PAD patients by addition of low-dose rivaroxaban to ASA monotherapy for 12 weeks.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04218656.

DELAYED-ONSET CORONARY VASOSPASM FOLLOWING RADIOFREQUENCY CATHETER ABLATION OF ATRIAL FIBRILLATION

DELAYED-ONSET CORONARY VASOSPASM FOLLOWING RADIOFREQUENCY CATHETER ABLATION OF ATRIAL FIBRILLATION

Carotid hemodynamic response to external pressure and comparison with induced-stenosis progression: a fluid-structure interaction study

Non-invasive stenosis detection has always been difficult. A new concept of applying external pressure over the artery was compared with stenosis growth in this computational study. When stenosis develops, the artery constricts, obstructing blood flow in that area. Under external pressure, the constricted artery behaves similarly. The current fluid-structure interaction study compares the hemodynamic parameters of a stenosed artery and an artery subjected to external pressure. Significant similarities were discovered when the velocity profile and arterial displacement for both scenarios were compared. This study can be used to characterise stenosis experimentally while remaining non-invasive.

Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in part from the complex nature of disease pathogenesis, with several signaling compounds known to be involved (e.g., endothelin-1, prostacyclins) which are indeed targets of PAH therapy. Over the last decade, potassium channelopathies were established as novel causes of PAH. More specifically, loss-of-function mutations in the KCNK3 gene that encodes the two-pore-domain potassium channel KCNK3 (or TASK-1) and loss-of-function mutations in the ABCC8 gene that encodes a key subunit, SUR1, of the ATP-sensitive potassium channel (KATP) were established as the first two potassium channelopathies in human cohorts with pulmonary arterial hypertension. Moreover, voltage-gated potassium channels (Kv) represent a third family of potassium channels with genetic changes observed in association with PAH. While other ion channel genes have since been reported in association with PAH, this review focuses on KCNK3, KATP, and Kv potassium channels as promising therapeutic targets in PAH, with recent experimental pharmacologic discoveries significantly advancing the field.

Cerebrovascular Effects of Alcohol Combined with Tetrahydrocannabinol.

Introduction: Alcohol (ethanol) and cannabis are among the most widely used recreational drugs in the world. With increased efforts toward legalization of cannabis, there is an alarming trend toward the concomitant (including simultaneous) use of cannabis products with alcohol for recreational purpose. While each drug possesses a distinct effect on cerebral circulation, the consequences of their simultaneous use on cerebral artery diameter have never been studied. Thus, we set to address the effect of simultaneous application of alcohol and (-)-trans-Δ-9-tetrahydrocannabinol (THC) on cerebral artery diameter. Materials and Methods: We used Sprague-Dawley rats because rat cerebral circulation closely mimics morphology, ultrastructure, and function of cerebral circulation of humans. We focused on the middle cerebral artery (MCA) because it supplies blood to the largest brain territory when compared to any other cerebral artery stemming from the circle of Willis. Experiments were performed on pressurized MCA ex vivo, and in cranial windows in vivo. Ethanol and THC were probed at physiologically relevant concentrations. Researchers were "blind" to experimental group identity during data analysis to avoid bias. Results: In males, ethanol mixed with THC resulted in greater constriction of ex vivo pressurized MCA when compared to the effects exerted by separate application of each drug. In females, THC, ethanol, or their mixture failed to elicit measurable effect. Vasoconstriction by ethanol/THC mixture was ablated by either endothelium removal or pharmacological block of calcium- and voltage-gated potassium channels of large conductance (BK type) and cannabinoid receptors. Block of prostaglandin production and of endothelin receptors also blunted constriction by ethanol/THC. In males, the in vivo constriction of MCA by ethanol/THC did not differ from ethanol alone. In females, the in vivo constriction of this artery by ethanol was significantly smaller than in males. However, artery constriction by ethanol/THC did not differ from the constriction in males. Conclusions: Our data point at the complex nature of the cerebrovascular effects elicited by simultaneous use of ethanol and THC. These effects include both local and systemic components.

Blood Flow Modeling in Constricted Arteries Under Body Acceleration and Wall Slip Using Two-Layered Bingham Plastic Fluid

Analysis is done on a two-layered Bingham Plastic model of restricted, thin arteries with periodic body acceleration. The model essentially consists of a centre layer with a core of suspended red blood cells and an outer layer with a peripheral plasma layer. It has been assumed that the rheology of blood in the core region has been classified as a Newtonian fluid with the PPL and a non-Newtonian fluid obeying the law of Bingham plastic model. This model has been used to investigate how blood flow in stenotic arteries is affected by body acceleration, the non-Newtonian character of blood, and a velocity slip at the wall. Analytical equations for axial velocity, flow rate, wall shear stress, and apparent viscosity are produced by using the perturbation method, and their variations with respect to various parameters are shown in the figures and explained in this article. Due to a wall slip, it is seen that while velocity and flow rate rise, effective viscosity falls. The impact of body acceleration significantly increases flow rates and speed. The physiological effects of this theoretical modelling for blood flow conditions are also briefly looked at.

Covid 19 vaccines and the misinterpretation of perceived side effects clarity on the safety of vaccines.

In the era of Covid 19 and mass vaccination programs, the anti-vaccination movement across the world is currently at an all-time high. Much of this anti-vaccination sentiment could be attributed to the alleged side effects that are perpetuated across social media from anti-vaccination groups. Fear mongering and misinformation being peddled by people with no scientific training to terrorise people into staying unvaccinated is not just causing people to remain susceptible to viral outbreaks, but could also be causing more side effects seen in the vaccination process. This brief review will offer data that may demonstrate that misinformation perpetuated by the anti-vaccination movement may be causing more deaths and side effects from any vaccine. A mini review of published literature has been conducted and found that mental stress clearly causes vasoconstriction and arterial constriction of the blood vessels. Therefore, if subjects are panicked, concerned, stressed or scared of the vaccination, their arteries will constrict and become smaller in and around the time of receiving the vaccine. This biological mechanism (the constriction of veins, arteries and vessels under mental stress) is the most likely cause for where there has been blood clots, strokes, heart attacks, dizziness, fainting, blurred vision, loss of smell and taste that may have been experienced shortly after vaccine administration. The extreme mental stress of the patient could most likely be attributed to the fear mongering and scare tactics used by various anti-vaccination groups. This paper does not aim to rule in or out every side effect seen, but it is highly likely that many apparent side effects seen shortly after a subject has received a vaccine could be the result of restricted or congested blood flow from blood vessel or arterial constriction caused by emotional distress or placebo based on fear around vaccines.

Reversible cerebral vasoconstriction syndrome: review of neuroimaging findings.

Reversible cerebral vasoconstriction syndrome (RCVS) is a group of disorders characterized by segmental narrowing and dilatation of medium-to-large cerebral arteries, clinically presenting with recurrent episodes of sudden-onset thunderclap headaches, with or without focal neurological deficits. Cerebral vasoconstriction is typically reversible, with spontaneous resolution within 3 months. Although the syndrome has generally a benign course, patients with neurological deficits may experience worse outcome. The main imaging finding is segmental constriction of intracranial arteries, which can be associated with subarachnoid hemorrhage and/or ischemic foci. Other possible findings are intracranial hemorrhage, subdural bleeding and cerebral edema. The latter may have a pattern which can resemble that of posterior reversible encephalopathy syndrome, a condition that can overlap with RCVS. New imaging techniques, such as vessel wall imaging and arterial spin labeling, are proving useful in RCVS and are giving new insights into the pathophysiology of this condition. In this paper, we aim to review neuroimaging findings of RCVS.

Reversible cerebral artery constriction accompanied with stroke-like episode in MELAS: A case series

ObjectiveThe pathophysiology of stroke-like episode (SLE) in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) was uncertain, though mitochondrial metabolic crisis of cortical neurons and mitochondrial proliferation in small vessels of brain have been considered. However, the involvement of major cerebral vessels was debated. We aimed to investigate whether major cerebral vessels participate in SLE. MethodsWe retrospectively collected the clinical and neuroimaging data of MELAS patients diagnosed in our center. Through follow-up, the cases harboring reversible cerebral artery constriction on brain magnetic resonance angiography (MRA) examination were included in this study. ResultsThere were 20 patients with intact brain MRA data at acute and non-acute phases. Only 3 cases with m.3243A > G mutation were enrolled. They suffered once or twice SLEs manifesting headache, blurred vision, seizures or mental and behavior disorder. New lesions were present in temporo-parietal and/or temporo-occipital regions. Segmental stenosis at middle cerebral artery and/or posterior cerebral artery, proximal portions in particular, was ipsilateral to the lesions at acute phase in all the 3 patients, which was resolved during the subacute or chronic stages. Moreover, the SLEs lesions were located within the stenotic arteries territory. In addition, dilation at distal portions of the stenotic arteries was observed at acute phase as well in 2 patients. ConclusionReversible constriction of cerebral arteries may contribute to SLE of MELAS. MELAS should be a differential diagnosis when stenosis of major cerebral vessels is present at acute phase of SLE.

Is there a role of proinflammatory cytokines on degenerin-mediated cerebrovascular function in preeclampsia?

Preeclampsia (PE) is associated with adverse cerebrovascular effects during and following parturition including stroke, small vessel disease, and vascular dementia. A potential contributing factor to the cerebrovascular dysfunction is the loss of cerebral blood flow (CBF) autoregulation. Autoregulation is the maintenance of CBF to meet local demands with changes in perfusion pressure. When perfusion pressure rises, vasoconstriction of cerebral arteries and arterioles maintains flow and prevents the transfer of higher systemic pressure to downstream microvasculature. In the face of concurrent hypertension, loss of autoregulatory control exposes small delicate microvessels to injury from elevated systemic blood pressure. While placental ischemia is considered the initiating event in the preeclamptic cascade, the factor(s) mediating cerebrovascular dysfunction are poorly understood. Elevated plasma proinflammatory cytokines, such as tumor necrosis factor α (TNF‐α) and interleukin‐17 (IL‐17), are potential mediators of autoregulatory loss. Impaired CBF responses to increases in systemic pressure are attributed to the impaired pressure‐induced (myogenic) constriction of small cerebral arteries and arterioles in PE. Myogenic vasoconstriction is initiated by pressure‐induced vascular smooth muscle cell (VSMC) stretch. Recent studies from our laboratory group indicate that proinflammatory cytokines impair the myogenic mechanism of CBF autoregulation via inhibition of vascular degenerin proteins, putative mediators of myogenic constriction in VSMCs. This brief review links studies showing the effect of proinflammatory cytokines on degenerin expression and CBF autoregulation to the pathological cerebral consequences of preeclampsia.

Myocardial infarction in pregnancy: Current topical issues in diagnostics and treatment

Lately due to the increase of childbearing age of women, high prevalence of cardiovascular diseases, and, presumably, due to the usage of some medications, there was an increase in myocardial infarction (MI) cases in pregnant women. Risk factors and pathophysiological mechanisms of MI in pregnant women differ from the general population, and are heterogeneous. Pregnancy and childbirth can be defined as ‘physiological stress’ for the cardiovascular system, which can cause MI. Abrupt changes in hemodynamics and increased coagulation state during pregnancy, in childbirth or in the early postpartum period can provoke sudden constriction (vasospasm) of a coronary artery (CA), as well as non-atherosclerotic spontaneous CA dissection, which leads to a critical decrease in the supply of oxygen to the heart muscle. The frequency of hemodynamically significant atherosclerosis of CA is also increasing. The incidence of maternal, perinatal mortality and obstetric complications is higher than in women without history of acute coronary syndrome. Over the past few decades, the diagnosis and treatment of myocardial infarction improved, the number of primary percutaneous coronary interventions in pregnant women increased, and there is now less inpatient mortality. However, due to the absence of large randomized clinical trials on the MI in pregnant women it is impossible to develop a unified algorithm for the management and preventive measures for this condition, thereby it is difficult to select an optimal treatment tactic, and hard to predict subsequent cardiovascular events. In this article we analyzed current data on MI during pregnancy, childbirth, and the postpartum period.

Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension.

Calcium influx from depolarized CaV1.2 calcium channels triggers the contraction of vascular smooth muscle cells (VSMCs), which is important for maintaining vascular myogenic tone and blood pressure. The function of CaV1.2 channel can be subtly modulated by alternative splicing (AS), and its aberrant splicing involves in the pathogenesis of multiple cardiovascular diseases. The RNA-binding protein Rbfox1 is reported to regulate the AS events of CaV1.2 channel in the neuronal development, but its potential roles in vascular CaV1.2 channels and vasoconstriction remain undefined. Here, we detect Rbfox1 is expressed in rat vascular smooth muscles. Moreover, the protein level of Rbfox1 is dramatically decreased in the hypertensive small arteries from spontaneously hypertensive rats in comparison with normotensive ones from Wistar-Kyoto rats. In VSMCs, Rbfox1 could dynamically regulate the AS of CaV1.2 exons 9* and 33. By whole-cell patch clamp, we identify knockdown of Rbfox1 induces the hyperpolarization of CaV1.2 current-voltage relationship curve in VSMCs. Furthermore, siRNA-mediated knockdown of Rbfox1 increases the K+-induced constriction of rat mesenteric arteries. In summary, our results indicate Rbfox1 modulates vascular constriction by dynamically regulating CaV1.2 alternative exons 9* and 33. Therefore, our work elucidates the underlying mechanisms for CaV1.2 channels regulation and provides a potential therapeutic target for hypertension.

Endovascular Intervention in a Narrowing Vessel of the Left Vertebral Artery with Bilateral Common Carotid Artery Occlusion and Aneurysm Rupture and Hemorrhage in the V4 Segment of the Right Vertebral Artery.

In this study, a case of bilateral common carotid artery occlusion and aneurysm in the V4 segment of the right vertebral artery with constriction of the left vertebral artery is presented. By improving digital subtraction angiography, an elderly female patient with subarachnoid haemorrhage (SAH) was diagnosed with a V4 segment of right vertebral artery aneurysm, a microaneurysm at the beginning of basilar aneurysms, bilateral common carotid artery occlusion, and narrowing vessel of left vertebral artery (DSA). Through the compensation of the basilar artery, the bilateral vertebral arteries provide intracranial and extracranial blood. Because the vertebral artery is narrowed, the right vertebral artery has priority in intracranial and extracranial blood delivery. Many members of the patient's immediate family have vasculitis, which has yet to be proven by appropriate laboratory testing but is thought to be the major cause of big artery occlusion. After cerebral angiography, the major source of this subarachnoid haemorrhage was determined to be a V4 segment of right vertebral artery aneurysm. Endovascular stent-assisted coil embolization was used to treat a V4 section of the right vertebral artery aneurysm. Because the basilar aneurysm was distal to the artery, interventional embolization was difficult to do, and it was not the major cause of the subarachnoid haemorrhage, the patient was advised to have follow-up surveillance, and she recovered well following the procedure. The combination of endovascular intervention of bilateral common carotid artery blockage and V4 segment of right vertebral artery aneurysm yielded excellent clinical outcomes in this instance. Endovascular treatment of a bilateral common carotid artery blockage paired with a V4 segment of a right vertebral artery aneurysm yielded excellent clinical outcomes in this patient, although long-term follow-up is necessary.

Internal Carotid Artery Constriction with or without Superficial Temporal Artery–Middle Cerebral Artery Bypass for Patients with Giant Internal Carotid Aneurysms

The optimal management of giant internal carotid aneurysms (GICAs) is disputed owing to their low incidence. The aim of this study was to describe the use of internal carotid artery (ICA) constriction as therapeutic management of GICAs. This retrospective cohort study analyzed data from medical histories and follow-up of 14 patients with GICAs. Before surgery, the patients underwent balloon test occlusion and magnetic resonance perfusion evaluation. ICA constriction was considered only for patients with negative balloon test occlusion. A transverse incision of about 50% of the initial part of the ICA was done, and the free margins on both sides were sutured, causing 70%-90% stenosis. ICA constriction alone was selected (11 cases) if both anterior communicating artery and posterior communicating artery compensatory blood flow existed and magnetic resonance perfusion was ≤II1 on the affected side. If there was only 1 compensatory vessel from the anterior communicating artery and posterior communicating artery, and/or magnetic resonance perfusion was >II1, ICA constriction was combined with low-flow bypass (3 cases). The mean follow-up time of the 14 patients was 43.5 months (interquartile range: 38.8-51.3 months). Of these 14 patients, 5 achieved O'Kelly-Marotta grades C and D. Clinical improvement occurred in 12 of 14 patients. No patients experienced new-onset stroke. ICA constriction exhibits a perforator protective effect. This procedure could be a promising alternative to ICA ligation in patients with GICAs and negative balloon test occlusion.

Aging Alters Integrin‐mediated Vascular Smooth Muscle Function in Soleus Feed Arteries

IntroductionPrevious data have shown that aging impairs vasomotor function and alters vascular smooth muscle cell (VSMC) properties. Integrins play an important role in regulating many cellular functions including arterial contractility. However, how aging affects integrin function, and their contribution to impaired constriction in aged arteries has not yet been elucidated. Thus, the purpose of this study was to investigate the age‐induced alteration of integrin function in isolated VSMC and in intact soleus muscle resistance arteries.MethodsSoleus muscle feed arteries (SFA) were isolated from young (4 mo) and old (24 mo) male Fischer 344 rats, cannulated with glass micropipettes and pressurized at 90cm H2O. Endothelial cells were removed (denuded) by passing 5 ml of air through the artery lumen. Vasoconstrictor responses were assessed by adding of norepinephrine (NE; 10‐9‐10‐4M), angiotensin II (Ang II; 10‐11‐10‐7 M), or phenylephrine (PE; 10‐9‐10‐4 M) in the presence or absence of RGD, an integrin inhibitory peptide. RGE, a non‐inhibitory peptide was used as control. To investigate changes in integrin expression and recruitment at focal adhesions with age, RT‐qPCR, cell adhesion assays, and total internal reflection fluorescence (TIRF) imaging were performed using VSMC isolated from young and old SFA.ResultsOld denuded SFA had reduced vasoconstrictor responses to NE, PE, and Ang II. In the presence of the RGD‐inhibitory peptide, constrictor responses to Ang II were significantly inhibited in denuded old vs. young SFA. Constrictor responses to NE and PE were not significantly altered by RGD. Constrictor responses to NE, PE, and Ang II were also not affected by RGE. Gene expression of specific integrins expressed by VSMC were downregulated in old VSMC compared to young. In addition, RGD‐treated VSMC showed decreased adhesion to fibronectin in both young and old VSMC compared to RGE non‐inhibitory peptide. Quantitative analysis of TIRF images showed that recruitment of integrin α5 and β3 was diminished in old VSMC while β1 was not altered with age.ConclusionsTaken together, these data suggest that aging leads to integrin dysfunction, which contributes to decreased contractile properties of vascular smooth muscle in SFA.

Inducible Smooth Muscle‐Specific Knockout of Acid Sensing Ion Channel 1 Protects Against Pulmonary Hypertension

Acid‐sensing ion channel 1 (ASIC1) is a proton‐gated cation channel that conducts both Na+ and Ca2+. ASIC1 is expressed in multiple cell types including vascular smooth muscle cells (SMCs) and endothelial cells (ECs). Our laboratory has previously shown that ASIC1 contributes to pulmonary arterial constriction and the development of chronic hypoxia (CH)‐induced pulmonary hypertension. However, the contribution of SMC versus EC ASIC1 to CH‐induced pulmonary hypertension is unknown. We tested the hypothesis that SMC expression of ASIC1 contributes to pulmonary hypertension and vascular remodeling by examining the development of CH‐induced pulmonary hypertension (barometric pressure of 380 mmHg for 6 weeks) in inducible SMC‐specific ASIC1 knockout (SMC‐Asic1‐/‐) and EC‐specific ASIC1 knockout (EC‐Asic1‐/‐) mice. The SMC‐Asic1‐/‐animals were used to examine the prevention and reversal of pulmonary hypertension by either inducing Asic1 knockout before CH exposure or following the establishment of pulmonary hypertension (3 weeks post‐CH). Pulmonary hypertension was assessed by direct cardiac puncture in anesthetized mice to measure right ventricular systolic pressure. Similar to global ASIC1 knockout (Asic1‐/‐) mice, SMC‐Asic1‐/‐ mice were protected from the development of CH‐induced pulmonary hypertension. In contrast, EC‐Asic1‐/‐ mice developed pulmonary hypertension comparable to wildtype Asic1+/+ mice (Figure 1). Furthermore, CH‐induced pulmonary hypertension was reversed by induction of SMC‐specific ASIC1 knockout following established pulmonary hypertension. CH‐induced vascular remodeling was assessed using smooth muscle α‐actin immunofluorescence to determine the medial thickness of small pulmonary arteries. The degree of arterial muscularization was significantly attenuated and/or reversed in SMC‐Asic1‐/‐ arteries (P<0.05). These findings were additionally supported by decreased CH‐induced proliferation (P<0.05) and migration (P<0.05) of pulmonary arterial SMC from Asic1‐/‐ mice, assessed by flow cytometry of BrdU positive cells and transwell migration assay, respectively. Together these data demonstrate that SMC, but not EC, ASIC1 contributes to CH‐induced pulmonary hypertension and vascular remodeling. Furthermore, these studies provide evidence for the therapeutic potential of ASIC1 inhibition to reverse pulmonary hypertension.

Advanced Maternal Age Impairs Uterine Artery Remodelling in the Pregnant Rat

Advanced maternal age (AMA, ≥35 years) pregnancies are increasingly common, and are at increased risk for pregnancy complications. We previously showed that ex vivo uterine artery constriction due to increasing intraluminal pressures (myogenic tone) was greater in arteries of AMA vs. young pregnant rats. Aging impairs vascular reactivity and increases vascular stiffness via structural changes (e.g. increased collagen), however, the impact of AMA on adaptations to pregnancy in the uterine artery is unknown. We hypothesized that functional and structural uterine artery adaptations to pregnancy are impaired in aged compared with young rats.Pregnant young (4 months) and aged (9 months; ~35 years in humans) rats were studied on gestational day 20 (term=22 days) with age‐matched non‐pregnant rats. Uterine arteries were isolated and mounted in a pressure myograph. Active tone (calcium present in buffer, n=6‐10) and mechanical properties (circumferential stress and strain; calcium absent, n=10‐24) were assessed. Myogenic tone, circumferential stress and strain were calculated from active and passive curves. Collagen and elastin in the tunica media and intima (combined) were visualized with Masson’s trichrome (collagen) or Verhoeff’s (elastin) stains (n=4‐6). Data are mean area under the curve (AUC, myography) or % positive area (histology) ± SEM; analyzed by two‐way ANOVA with Sidak post‐hoc tests (significance: p<0.05).Between 4‐100 mmHg, myogenic tone did not change with age or pregnancy. However, arteries from young pregnant rats displayed forced vasodilation at higher pressures (100‐160 mmHg) that did not occur in arteries from other groups (p<0.0001). Circumferential stress and strain (Figure 1) increased with pregnancy (p<0.0001) but was significantly lower in arteries from pregnant AMA compared to young pregnant dams (p<0.05). Collagen and elastin (% positive areas) did not change with age or pregnancy overall, however, arteries from young non‐pregnant rats had greater collagen:elastin ratios than those from aged non‐pregnant rats (p=0.021). Arteries from aged non‐pregnant, young pregnant and AMA rats had similar ratios.This study illustrates that aging impacts both structural and functional adaptations of uterine arteries during pregnancy. The lower compliancy of arteries from AMA rats may be due to increased crosslinking of the existing collagen within the artery, as it was not explained by collagen:elastin ratio. These structural differences may contribute to the functional differences, potentially reducing uteroplacental blood supply. Thus, impaired uterine artery adaptations may increase the risk of pregnancy complications in women of advanced age.

Statins stimulate voltage‐gated Ca2+ channels in arterial smooth muscle cells to induce rapid vasoconstriction in resistance‐size cerebral arteries

Statins are cholesterol‐lowering drugs with a range of beneficial vascular effects. Vascular effects are believed to result from long‐term statin therapy and reduction of cholesterol and mevalonate biosynthesis, and the inhibition of mevalonate‐dependent Rho/ROCK signaling. However, no studies have investigated the direct effects of acute statin application on fresh isolated resistance cerebral arteries using therapeutic concentrations of statins. Here, we examined acute vascular effects of rosuvastatin and simvastatin on Sprague Dawley rat cerebral arteries and underlying molecular mechanisms. We used pressurized arterial myography, simultaneous measurement of vessel Ca2+ fluorescence and diameter, pharmacological modulation, RNAi, Western blotting and biotinylation. Intravascular pressure in the mounted cerebral artery segments was gradually increased to 60 mmHg to stimulate the development of myogenic tone. At 60 mmHg, cerebral arteries developed ~36% myogenic tone, after which a cumulative dose response (0.01‐1000 nM) to rosuvastatin was performed and diameter changes recorded. Our data shows that, at 0.1, 1 and 10 nM concentrations, rosuvastatin induced a potent vasoconstriction – an observation never reported previously with any statin. Intriguingly, rosuvastatin, at 100 nM and 1000 nM concentrations (supratherapeutic), abolished myogenic tone and caused robust vasodilation. Rosuvastatin‐induced vasoconstriction reached a plateau at 1 nM concentration, which was used as reference for mechanistic studies. Within 2‐3 minutes of application, rosuvastatin and simvastatin constricted cerebral arteries by ~26 μm and ~24 μm, respectively. Endothelium denudation (intact ~23 μm vs denuded ~25 μm), or mevalonate supplementation did not alter statin‐induced vasoconstriction (control ~28 μm vs mevalonate ~29 μm), suggesting endothelium‐ and HMG‐CoA reductase‐independent mechanism. In contrast, removal of extracellular Ca2+with EGTA (~6 μm) or the application of nimodipine (~5 μm), a selective blocker of smooth muscle cell voltage‐gated Ca2+ channel, CaV1.2, or siRNA knockdown of CaV1.2 each abolished cerebral artery vasoconstriction and reduced [Ca2+]i, indicating that the Ca2+ entry through CaV1.2 plays a critical role here. Application of thapsigargin, a blocker of SR/ER membrane Ca2+‐ATPase pump, SERCA, but not ryanodine, a blocker of ryanodine receptor‐mediated Ca2+ release, fully reversed statin‐induced cerebral artery constriction and reduced [Ca2+]i. Arterial biotinylation data showed that short‐term statin exposure did not alter the surface expression, distribution and function of CaV1.2 channels.Altogether, our data demonstrate that statins at therapeutic concentrations directly stimulate smooth muscle cell CaV1.2 and Ca2+ influx to induce rapid vasoconstriction in resistance cerebral arteries.