Christian Aalkjaer

Aarhus University | AU · Department of Biomedicine

Objectives: To examine whether colchicine improves β adrenoceptor-mediated vasodilation in humans by conducting a double-blinded, placebo controlled intervention study. Background: Colchicine treatment has known beneficial effects on cardiovascular health and reduces the incidence of cardiovascular disease. Studies in isolated rodent arteries ha...

Background: A variant in the SLC4A3 anion exchanger has been identified as a novel cause of short QT syndrome (SQTS), but the clinical importance of SLC4A3 as a cause of SQTS or sudden cardiac death (SCD) remains unknown. Objective: To investigate the prevalence of potential disease-causing variants using gene panels including SLC4A3. Methods:...

Purpose: Vasomotion is spontaneous oscillations in the diameter of resistance vessels with derived effects on blood flow, and it has been proposed that disturbances in vasomotion may be involved in retinal vascular disease. The purpose of this study was to investigate whether retinal vasomotion shows regional variation and is modified by activated...

Background: Several local Ca ²⁺ events are characterized in smooth muscle cells. We have previously shown that an inhibitor of the Na,K-ATPase, ouabain induces spatially restricted intracellular Ca ²⁺ transients near the plasma membrane, and suggested the importance of this signaling for regulation of intercellular coupling and smooth muscle cell c...

Giraffes are the highest living animals on Earth and therefore are challenged by gravity more than any other species. In particular the cardiovascular system needs to adapt to this challenge. Giraffes have a mean blood pressure around 200 mmHg, which ensures a mean arterial pressure near the head of 100 mmHg when the giraffe is standing with the ne...

Background Mutations in ATP1A2 gene encoding the Na,K‐ATPase α 2 isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K‐ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for hea...

Background The purine adenosine triphosphate (ATP) plays a significant role in retinal blood flow regulation and recent evidence suggests that the vasoactive effect of the compound differs in vessels at different branching level. However, the cellular basis for the regulation of retinal blood flow mediated by ATP has only been scarcely studied. Me...

The evolved adaptations of other species can be a source of insight for novel biomedical innovation. Limitations of traditional animal models for the study of some pathologies are fueling efforts to find new approaches to biomedical investigation. One emerging approach recognizes the evolved adaptations in other species as possible solutions to hum...

Gravity affects the physiology of many animals, and the effect is, for good reason, most pronounced in tall species. The physiology—in particular, cardiovascular function—of giraffes has therefore captivated the interest of physiologists for centuries. Several studies document high mean arterial blood pressure of giraffes of about 200 mm Hg. This a...

Unique cardiovascular adaptations in giraffes (Giraffa Camelopardalis reticulata) have been the focus of numerous investigation for almost a century. The vertical distance between the heart and brain impose high pressure on the giraffe left ventricle leading to thickening that exceeds heart in other mammals. Yet, cardiovascular function appears to...

The neurovascular coupling ensures that cerebral activity is matched by the relevant blood flow. The control of the blood flow is mediated by capillaries and by the precapillary aterioles. It is the tone of the mural cells, which include pericytes, smooth muscle cells and cells with intermediate phenotypes between pericytes and smooth muscle cells,...

Small arteries, which play important roles in controlling blood flow, blood pressure and capillary pressure, are under nervous influence. Their innervation is predominantly sympathetic and sensory-motor in nature and while some arteries are densely innervated others are only sparsely so. Innervation of small arteries is a key mechanism in regulatin...

pH influences neuronal development and function. Despite a widespread expression pattern in the central nervous system, the role of the sodium bicarbonate cotransporter NBCn1/Slc4a7 has not been investigated for locomotor activity, emotion and cognition. Here, we addressed the behavioral consequences of NBCn1 knockout and evaluated hearing and visi...

A Ca2+ -activated Cl- channel protein, ANO1, is expressed in vascular smooth muscle cells where Cl- current is thought to potentiate contraction by contributing to membrane depolarization. However, there is an inconsistency between previous knockout and knockdown studies on ANO1's role in small arteries. In this study, we assessed cardiovascular fu...

Heart failure with preserved ejection fraction (HFpEF) is a leading form of human cardiovascular disease and commonly associated with systemic hypertension. Unique evolved adaptations in giraffe myocardia may be a natural animal model of resistance to HFpEF. In humans, pressure-overload induced left ventricular thickening (PLVT) impairs diastolic r...

Purpose: Adenosine triphosphate (ATP) is involved in the diameter regulation of retinal vessels. The compound has been shown to induce both constriction and dilatation, but the detailed mechanisms underlying these effects and the site of action of the compound are not known in detail. Therefore, the purpose of the present study was to investigate...

The previous reports on an addiction vulnerability marker in the human SLC4A7 gene encoding the Na/HCO3 transporter NBCn1 suggest that this pH-regulating protein may affect alcohol-related behavior and response. Here, we examined alcohol consumption and sensitivity to the sedative effects of alcohol in male NBCn1 knockout mice. These mice displayed...

We investigated whether sex differences exist in cyclooxygenase‐dependent effects on membrane potential and relaxation in mice mesenteric resistance arteries. Mesenteric small arteries of 9‐12‐week‐old, male and female, wild‐type mice, db/+ mice and diabetic db/db mice were mounted in myographs for measurements of isobaric diameter and smooth muscl...

Aims: Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypo- and hyperperfusion. FHM2 is associated with mutations in the Na,K-ATPase α2 isoform. Heterozygous mice bearing one of these mutations (α2+/G301R) were shown to have elevated cerebrovascular tone and, thus, hypoperfusion that migh...

Background: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte β3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. Objective: We have investigated the effects of PVAT on vessel dia...

Aim This study aimed to assess intracellular Ca²⁺ dynamics in nerve cells and Schwann cells in isolated rat resistance arteries and determine how these dynamics modify noradrenaline release from the nerves and consequent force development. Methods Ca²⁺ in nerves was assessed with confocal imaging, noradrenaline release with amperometry, and artery...

Key points: The prevailing dogma about neurogenic regulation of vascular tone consists of major vasodilatation caused by CGRP (and possibly substance P) released from sensory-motor nerves and vasoconstriction caused by noradrenaline, ATP and neuropeptode Y release from sympathetic nerves. Most studies on perivascular nerve-mediated vasodilatation...

Diabetic retinopathy is characterized by retinal lesions related to disturbances in retinal blood flow. The metabolic dysregulation in diabetes involves hyperglycemia which in both clinical and experimental studies has been shown to induce dilatation of larger retinal vessels, which has been suggested to be mediated by nitric oxide (NO). However, t...

Inhibition of the Na,K-ATPase by ouabain potentiates vascular tone and agonist-induced contraction. These effects of ouabain varies between different reports. In this study, we assessed whether the pro-contractile effect of ouabain changes with arterial diameter and the molecular mechanism behind it. Rat mesenteric small arteries of different diame...

Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point-mutations in the Na,K-ATPase α2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2+/−G301R) with wi...

Aims: The Na,K-ATPase is involved in a large number of regulatory activities including cSrc-dependent signalling. Upon inhibition of the Na,K-ATPase with ouabain, cSrc activation is shown to occur in many cell types. This study tests the hypothesis that acute potentiation of agonist-induced contraction by ouabain is mediated through Na,K-ATPase-cS...

TMEM16A is essential for Ca2+ -activated Cl- channel conductance in vascular smooth muscle. The importance of TMEM16A for agonist-induced vascular constriction and blood pressure control is, however, under debate. Previous studies suggested that TMEM16A might have a complex cellular function beyond being essential for the Ca2+ -activated Cl- conduc...

Microtubules can regulate GPCR (G protein-coupled receptor) signaling in various cell types. In vascular smooth muscle, activation of the β-adrenoceptor leads to production of cAMP to mediate a vasorelaxation. Little is known about the role of microtubules in smooth muscle, and given the importance of this pathway in vascular smooth muscle cells, w...

Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain <25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduce...

Background and purpose: Kv7.4 and Kv7.5 channels are regulators of vascular tone. 4-aminopyridine (4-AP) is considered a broad inhibitor of voltage-gated potassium (KV ) channels, with little inhibitory effect on Kv7 family members at millimolar concentrations. However, the effect of 4-AP on Kv7 channels has not been systematically studied. The ai...

Background and purpose: Phosphodiesterase 1 (PDE1), a subfamily of cyclic nucleotide phosphodiesterases consisting of three isoforms, PDE1A, PDE1B, and PDE1C, has been implicated in regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform-preferring PDE1 inhibitors, Lu AF58027, Lu AF64196...

Purpose A novel population of perivascular cells (PVC) is located immediately external to the vascular smooth muscle cells of retinal arterioles, express immunoreactivity to the pericyte marker NG2 and give rise to processes that extend into the retina. This suggests that PVCs could play a role in neurovascular coupling. However, the anatomical bas...

This study evaluated the accuracy of pulse oximetry, capnography, and oscillometric blood pressure during general anesthesia in giraffes (Giraffa camelopardalis). Thirty-two giraffes anesthetized for physiologic experiments were instrumented with a pulse oximeter transmittance probe positioned on the tongue and a capnograph sampling line placed at...

Modulation of endothelial calcium-activated K⁺ channels has been proposed as an approach to restore arterial endothelial cell function in disease. We hypothesized that small-conductance calcium-activated K⁺ channels (KCa2.3 or SK3) contributes to erectile function. The research was performed in transgenic mice with overexpression (KCa2.3T/T(−Dox))...

Functioning of the heart as a mechanical pump depends on electrical impulse formation in the sinus node, conduction of the excitatory wave along its preformed pathways, and orderly repolarisation. This article is protected by copyright. All rights reserved.

Key points: Substantial information on rat mesenteric small artery physiology and pharmacology based on in vitro experiments is available. Little is known about the relevance of this for artery function in vivo. We here present an intravital model where rat mesenteric small artery diameters are studied under isolated and controlled conditions in s...

Background: Hypoxia induced relaxation of larger retinal arterioles has been shown to be mediated by nitric oxide (NO) and cyclo-oxygenase (COX) products both in vivo and in vitro. However, the involvement of smaller retinal vessels in the response is unknown. Therefore, the purpose of the present study was to investigate the effect of blocking th...

Background: Mesenteric lymphatic vessels (MLVs) from various animal species have been intensively studied. We aimed to establish the viability and basic contractile characteristics of human MLVs maintained in vitro and to determine the reactivity of MLVs with norepinephrine (NE) and substance P (SP) and to compare with the thoracic duct (TD). Met...

Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na⁺/HCO3 co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells....

Background Patients with chronic kidney disease have a markedly increased cardiovascular mortality compared with the general population. Long chain n-3 polyunsaturated fatty acids have been suggested to possess cardioprotective properties. This cross-sectional and comparative study evaluated correlations between hemodynamic measurements, resistance...

We investigated the acute effects of glucagon-like peptides-1 (GLP-1), GLP-1(1-36) and GLP-1(7-36) on vascular endothelial growth factor-A (VEGFA)-induced endothelium-dependent signaling and vasodilation. Our hypothesis was that GLP-1 released from intestinal L-cells modulates processes related to PLCγ activation, Src and eNOS signaling, thereby co...

Cl⁻ and HCO3⁻ are the most prevalent membrane-permeable anions in the intra- and extracellular spaces of the vascular wall. Outwardly directed electrochemical gradients for Cl⁻ and HCO3⁻ permit anion channel opening to depolarize vascular smooth muscle and endothelial cells. Transporters and channels for Cl⁻ and HCO3⁻ also modify vascular contracti...

Aims: Arterial remodeling can cause luminal narrowing and obstruct blood flow. We tested the hypothesis that cellular acid-base transport facilitates proliferation and migration of vascular smooth muscle cells (VSMCs) and enhances remodeling of conduit arteries. Methods and results: Na(+),HCO3 (-)-cotransport via NBCn1 (Slc4a7) mediates net acid...

Purpose: Disturbances in the diameter regulation of the larger retinal vessels are involved in the pathophysiology of a number of vision threatening retinal diseases, but the role of the smaller vessels has received less attention. Therefore, an experimental model was developed for studying diameter changes in retinal vessels at all branching leve...

Introduction: The vascular resistance of stem villous arteries is determined by the balance between different contractile and relaxant agents and in the utero-placental circulation. Thromboxane A2 (TxA2), prostaglandin F2α (PGF2α) and endothelin-1 (ET-1) are considered to be among the most important contractile factors. However, it is not known if...

Giraffes – the tallest extant animals on Earth – are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. The pressure which may exceed 300 mmHg has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe...

We investigate sensing and signaling mechanisms for H+, HCO3- and CO2 in basilar arteries using out-of-equilibrium solutions. Selectively varying pHo, [HCO3-]o, or pCO2, we find: (a) lowering pHo attenuates vasoconstriction and vascular smooth muscle cell (VSMC) Ca2+-responses whereas raising pHo augments vasoconstriction independently of VSMC [Ca2...

The nature of NO- and COX-independent endothelial hyperpolarization (EDH) is not fully understood but activation of small- and intermittent-conductance Ca2+-activated K+ channels (SKCa and IKCa) is important. Previous studies have suggested that the significance of IKCa depends on Ca2+out. Also it has been suggested that K+ is important through loc...

We aimed at assessing the role of endothelial cell calcium for the endothelial dysfunction of mesenteric resistance arteries of db/db mice (a model of type 2 diabetes) and determine whether treatment with sulfaphenazole, improves endothelial calcium signaling and function. Pressure myography was used to study acetylcholine (ACh) -induced vasodilati...

Major depression is known to be associated with cardiovascular abnormalities and oxidative stress has been suggested to play a role. We tested the hypothesis that antidepressant treatment reduces oxidative stress, and endothelial dysfunctions in the chronic mild stress (CMS) model of depression in rats. Rats with >30% reduction in sucrose intake af...

The cellular basis for the regulation of retinal blood flow is unknown, but recently a new type of perivascular cell (PVC) with pericyte characteristics was identified in the retinal arterial vascular wall located immediately external to the vascular smooth muscle cells. A possible involvement of this cell type in the regulation of retinal vascular...

Voltage-gated sodium channels (VGSC) play a key role for initiating action potentials (AP) in excitable cells. VGSC in human lymphatic vessels have not been investigated. In this study we describe the electrical activity and action potentials of small human lymphatic collecting vessels as well as mRNA expression and function of VGSC in small and la...

Background The tallest animal on Earth, the giraffe (Giraffa camelopardalis) is endowed with a mean arterial blood pressure (MAP) twice that of other mammals. The kidneys reside at heart level and show no sign of hypertension related damage. We hypothesized that a species-specific evolutionary adaption in the giraffe kidney allows normal for size r...

Ca(2+)-activated Cl(-) channels (CaCCs) have numerous functions in the body and are potential players in the control of blood pressure. The CaCCs represent a heterologous group including at least two protein families; TMEM16 and bestrophins. CaCCs expression has been shown in the kidney, the heart and blood vessels. Agonist-stimulated Ca(2+)-activa...

Giraffes are the tallest living animals and endowed with the highest arterial blood pressure of any animal on Earth. Here we present novel data on kidney function in this extraordinary animal obtained over the course of two major expeditions in 2010 and 2012. As expected, the anaesthetised giraffes had very high mean arterial blood pressure ranging...

Major depression and cardiovascular diseases are two of the most prevalent health problems in western society and an association between them is generally accepted. Although the specific mechanism behind this comorbidity remains to be elucidated, it is clear that it has a complex multifactorial character including a number of neuronal, humoral, imm...

Cation-coupled HCO3(-) transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3(-) and associated with Na(+) and Cl(-) movement. The first Na(+)-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs i...

The carbonic anhydrase inhibitor dorzolamide can induce relaxation of retinal arterioles with a consequent increase in blood flow and oxygenation of the retina. It has been shown that the mechanisms underlying this relaxation are independent of extracellular acidosis and CO2. The purpose of the present study was to investigate the possible involvem...

Calcium channel blockers (CCB) are widely-prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We obser...

The presence of Ca(2+)-activated Cl(–) currents (I(Cl(Ca))) in vascular smooth muscle cells (VSMCs) is well established. ICl(Ca) are supposedly important for arterial contraction by linking changes in [Ca(2+)]i and membrane depolarization. Bestrophins and some members of the TMEM16 protein family were recently associated with I(Cl(Ca)). Two distinc...

Aim: A decrease in the Ca(2+) sensitivity of smooth muscle contraction is a hallmark of functional remodelling of blood vessels during development. However, the responsible factors are largely unknown. Here, we tested the hypothesis that the post-natal decline of arterial Ca(2+) sensitivity is the result of trophic effects of sympathetic nerves....

Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including "anhedonia"), whereas others are stress resilient. After 8 weeks of chr...

In smooth muscle cells, potassium permeability is high and this highly influences the resting membrane potential. Lymph propulsion is dependent on phasic contractions generated by the smooth muscle cells of lymphatic vessels and it is likely that potassium channels play a critical role in regulating contractility in this tissue. The aim of this stu...

Cardiovascular disease is the leading cause of death in patients with end stage renal disease (ESRD). The vasodilator mechanisms in small resistance arteries are in earlier studies shown to be reduced in patients with end stage renal disease. We studied whether endothelium dependent vasodilatation were diminished in ESRD patients and the interactio...