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Papers by Paul Fransen

American Journal of Physiology-Heart and Circulatory Physiology

Alzheimer's disease (AD) has long been considered a brain-specific dementia syndrome. However... more Alzheimer's disease (AD) has long been considered a brain-specific dementia syndrome. However, in recent decades the occurrence of cardiovascular (CV) disease in the progression of AD has been confirmed by increasing epidemiological evidence. In this study, we conducted an in-depth cardiovascular characterization of a humanized APP overexpressing mouse model (hAPP23+/-), which overexpresses the Swedish mutation (KM670/671NL). At the age of 6 months, hAPP23+/- mice had a lower survival, lower body weight and increased corticosterone and VMA levels compared to C57BL/6 littermates. Systolic blood pressure was increased in hAPP23+/- animals compared to C57BL/6 littermates, but diastolic blood pressure was not statistically different. Pulse pressure remained unchanged but abdominal and carotid pulse wave velocity (aPWV and cPWV) were increased in hAPP23+/- compared to C57BL/6 mice. Echocardiography showed no differences in systolic or diastolic cardiac function. Ex vivo evaluation of...

Circulation

Introduction: Arterial stiffness (AS) has gained much recognition as a hallmark and independent p... more Introduction: Arterial stiffness (AS) has gained much recognition as a hallmark and independent predictor of cardiovascular (CV) events. Although generally assumed to be an adaptive response to increased blood pressure (BP), AS precedes hypertension in at least two experimental mouse models, thus revealing an incomplete understanding of AS pathophysiology. Methods: The current study presents the longitudinal CV characterization of spontaneously ageing C57Bl6 mice (2, 4, 6, 9, 12 and 24-month old) (male, n>8). In vivo analysis of peripheral BP (Coda), aortic pulse wave velocity (aPWV, Vevo2100), and echocardiography (Vevo2100) was combined with ex vivo aortic studies of isometric reactivity (organ baths) and AS measurements in the Rodent Oscillatory Tension set-up for Arterial Compliance (ROTSAC). (Data are presented as mean ± SEM.) Results: In vivo and ex vivo characterisation confirms that aortic stiffness precedes peripheral BP alterations in spontaneously ageing C57Bl6 mice, w...

Frontiers in Physiology

Induction of hypertension by angiotensin II (AngII) is a widely used experimental stimulus to stu... more Induction of hypertension by angiotensin II (AngII) is a widely used experimental stimulus to study vascular aging in mice. It is associated with large artery stiffness, a hallmark of arterial aging and a root cause of increased cardiovascular risk. We reported earlier that long term (4 week) AngII treatment in mice altered the active, contractile properties of the arteries in a vascular bed-specific manner and that, in healthy mice aorta, active contractile properties of the aortic wall determine isobaric aortic stiffness. Given the huge physiological relevance of large artery stiffening, we aimed to characterize the early (1 week) changes in the active properties of the aorta of AngII-treated mice. We were not able to detect a significant effect of AngII treatment on anesthetized blood pressure or abdominal aorta pulse wave velocity. Ex vivo biomechanical and functional studies of the aorta revealed increased arterial stiffness and altered vascular smooth muscle cell (VSMC) and endothelial cell reactivity. Interestingly, the AngII-associated changes in the aorta could be largely attributed to alterations in basal VSMC tone and basal nitric oxide efficacy, indicating that, besides structural remodeling of the arterial wall, dysfunctional active components of the aorta play a crucial role in the pathophysiological mechanisms by which AngII treatment induces arterial stiffness.

Frontiers in physiology, 2017

Most vaso-reactive studies in mouse aortic segments are performed in isometric conditions and at ... more Most vaso-reactive studies in mouse aortic segments are performed in isometric conditions and at an optimal preload, which is the preload corresponding to a maximal contraction by non-receptor or receptor-mediated stimulation. In general, this optimal preload ranges from about 1.2 to 8.0 mN/mm, which according to Laplace's law roughly correlates with transmural pressures of 10-65 mmHg. For physiologic transmural pressures around 100 mmHg, preloads of 15.0 mN/mm should be implemented. The present study aimed to compare vascular reactivity of 2 mm mouse (C57Bl6) aortic segments preloaded at optimal (8.0 mN/mm) vs. (patho) physiological (10.0-32.5 mN/mm) preload. Voltage-dependent contractions of aortic segments, induced by increasing extracellular K(+), and contractions by α1-adrenergic stimulation with phenylephrine (PE) were studied at these preloads in the absence and presence of L-NAME to inhibit basal release of NO from endothelial cells (EC). In the absence of basal NO relea...

The Journal of physiology, Jan 3, 2016

Cyclic stretch is a major contributor of vascular function. However, isolated mouse aortas are fr... more Cyclic stretch is a major contributor of vascular function. However, isolated mouse aortas are frequently studied at low stretch frequency or even isometric conditions. Pacing experiments in rodents and humans show that arterial compliance is stretch frequency-dependent. The Rodent Oscillatory Tension Set-up to study Arterial Compliance is an in-house developed organ bath set-up that clamps aortic segments to imposed preloads at physiological rates up to 600 bpm. The technique enables us to derive pressure-diameter loops and assess biomechanical properties of the segment. To validate the applicability of this set-up we aimed to confirm the effects of distension pressure and vascular smooth muscle tone on arterial stiffness. At physiological stretch frequency (10 Hz), Peterson modulus (293 (10) mmHg) for wild-type mouse aorta increased 22% upon a rise in pressure from 80-120 mmHg to 100-140 mmHg, while, at normal pressure, Ep increased 80% upon maximal contraction of the vascular smo...

Frontiers in physiology, 2015

In the last decades, the search for mechanisms underlying progressive arterial stiffening and for... more In the last decades, the search for mechanisms underlying progressive arterial stiffening and for interventions to avoid or reverse this process has gained much attention. In general, arterial stiffening displays regional variation and is, for example, during aging more prominent in elastic than in muscular arteries. We hypothesize that besides passive also active regulators of arterial compliance [i.e., endothelial and vascular smooth muscle cell (VSMC) function] differ between these arteries. Hence, it is conceivable that these vessel types will display different time frames of stiffening. To investigate this hypothesis segments of muscular arteries such as femoral and mesenteric arteries and elastic arteries such as the aorta and carotid artery were isolated from female C57Bl6 mice (5-6 months of age, n = 8). Both microscopy and passive stretching of the segments in a myograph confirmed that passive mechanical properties (elastin, collagen) of elastic and muscular arteries were s...

Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues - From Molecules to Humans, 2012

Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues-From Molecu... more Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues-From Molecules to Humans 70 (NO) may be involved in these processes. Inhibition of endothelial NO synthase (eNOS) with N Ω-nitro-L-arginine methyl ester (L-NAME) or N Ω-nitro-L-arginine (L-NNA) causes hypertension and the decrease of basal endothelial NO release or availability may be at the basis of increased reactivity to vasoconstrictors in hypertension (Panza et al., 1993). Furthermore, in the beginning of plaque development in animal models and in patients with atherosclerotic symptoms or risk factors, eNOS activity and concomitant NO release is altered, especially in atherosclerosis-prone aortic segments (Fransen et al., 2008; Kauser et al., 2000; Vanhoutte et al., 2009). Recently, we showed that L-type Ca 2+ influx and its inhibition with CaBs may also have consequences for the capacity of NO to relax constricted mouse aorta. The relaxing efficacy of NO in mouse aorta was dependent on the contractile agonist, and more specifically, decreased when the contraction was mainly elicited via L-type Ca 2+ influx, but increased when Ca 2+ influx was partially inhibited with CaBs (Van Hove et al., 2009). The above observations may suggest an interaction between basal NO and VSMC Ltype Ca 2+ channels. An inhibitory effect of NO on Ca 2+ currents in vascular smooth muscle and cardiomyocytes has been described (Blatter & Wier, 1994; Fischmeister et al., 2005; Tsai & Kass, 2009), but has not been associated with L-type Ca 2+ channel-mediated contractions in mouse aorta. This chapter will focus on the specific role of L-type Ca 2+ channels in vasoconstriction and dilation and the interplay between NO and these L-type Ca 2+ channels. Contraction by Ca 2+ Influx via the L-Type Ca 2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide 71

European Journal of Pharmacology, 2015

α1-Adrenoceptor stimulation of mouse aorta causes intracellular Ca(2+) release from sarcoplasmic ... more α1-Adrenoceptor stimulation of mouse aorta causes intracellular Ca(2+) release from sarcoplasmic reticulum Ca(2+) stores via stimulation of inositoltriphosphate (IP3) receptors. It is hypothesized that this Ca(2+) release from the contractile and IP3-sensitive Ca(2+) store is under the continuous dynamic control of time-independent basal Ca(2+) influx via L-type voltage-gated Ca(2+) channels (LCC) residing in their window voltage range. Mouse aortic segments were α1-adrenoceptor stimulated with phenylephrine in the absence of external Ca(2+) (0Ca) to measure phasic isometric contractions. They gradually decreased with time in 0Ca, were inhibited with 2-aminoethoxydiphenyl borate, and declined with previous membrane potential hyperpolarization (levcromakalim) or with previous inhibition of LCC (diltiazem). Former basal stimulation of LCC with depolarization (15mM K(+)) or with BAY K8644 increased the subsequent phasic contractions by phenylephrine in 0Ca. Although exogenous NO (diethylamine NONOate) reduced the phasic contractions by phenylephrine, stimulation of endothelial cells with acetylcholine in 0Ca failed to attenuate these phasic contractions. Finally, inhibition of the basal release of NO with N(Ω)-nitro-L-arginine methyl ester also attenuated the phasic contractions by phenylephrine. Results indicated that α1-adrenoceptor stimulation with phenylephrine causes phasic contractions, which are controlled by basal LCC and endothelial NO synthase activity. Endothelial NO release by acetylcholine was absent in 0Ca. Given the growing interest in the active regulation of arterial compliance, the dependence of contractile SR Ca(2+) store-refilling in basal conditions on the activity of LCC and basal eNOS may contribute to a more thorough understanding of physiological mechanisms leading to arterial stiffness.

American journal of physiology. Heart and circulatory physiology, Jan 15, 2015

Autophagy is an evolutionary preserved process that prevents the accumulation of unwanted cytosol... more Autophagy is an evolutionary preserved process that prevents the accumulation of unwanted cytosolic material through the formation of autophagosomes. Although autophagy has been extensively studied to understand its function in normal physiology, the role of vascular smooth muscle (SM) cell (VSMC) autophagy in Ca(2+) mobilization and contraction remains poorly understood. Recent evidence shows that autophagy is involved in controlling contractile function and Ca(2+) homeostasis in certain cell types. Therefore, autophagy might also regulate contractile capacity and Ca(2+)-mobilizing pathways in VSMCs. Contractility (organ chambers) and Ca(2+) homeostasis (myograph) were investigated in aortic segments of 3.5-mo-old mice containing a SM cell-specific deletion of autophagy-related 7 (Atg7; Atg7(fl/fl) SM22α-Cre(+) mice) and in segments of corresponding control mice (Atg7(+/+) SM22α-Cre(+)). Our results indicate that voltage-gated Ca(2+) channels (VGCCs) of Atg7(fl/fl) SM22α-Cre(+) VSM...

European journal of pharmacology, Jan 5, 2014

L-type calcium channel blockers (LCCBs) reduce blood pressure more effectively in hypertensive th... more L-type calcium channel blockers (LCCBs) reduce blood pressure more effectively in hypertensive than in normotensive subjects and are more effective in vascular smooth muscle (VSM) than in cardiac muscle. This has been explained by the depolarized resting potential of VSM in comparison with heart muscle cells and during hypertension, because both favor the "high affinity" inactivated state of the L-type calcium channel (LCC). Depolarized resting potentials, however, also increase Ca(2+) influx via window, non-inactivating LCC. The present study investigated whether these channels can be effectively blocked by nifedipine, verapamil or diltiazem, as representatives of different LCCB classes. C57Bl6 mouse aortic segments were depolarized by 50mM K(+) to attain similar degree of inactivation. The depolarization evoked biphasic contractions with the slow force component displaying higher sensitivity to LCCBs than the fast component. Removal of the fast force component increased,...

Clinical Therapeutics, 2014

Arterial stiffening is a well-known risk factor for cardiovascular complications, including myoca... more Arterial stiffening is a well-known risk factor for cardiovascular complications, including myocardial infarction, left ventricular hypertrophy, stroke, renal failure, dementia, and death. The most important in vivo parameter of arterial stiffness is pulse wave velocity (PWV). Clinically, PWV is determined noninvasively by using applanation tonometry. Unlike the clinical value of arterial stiffness and PWV, techniques to determine PWV in mice are scarce. The only way to determine aortic PWV noninvasively in the mouse is by using ultrasound echo Doppler velocimetry. It is a fast, efficient, and accurate technique, but the required tools are expensive and technically complex. Here, we describe the development and validation of a novel technique to assess carotid-femoral PWV (cfPWV) noninvasively in mice. This technique is based on applanation tonometry as used in clinical practice. We were able to establish a reproducible reference value in wild-type mice (3.96 [0.05] m/s) and to detect altered cfPWV values in endothelial nitric oxide synthase knockout (eNOS-/-) mice (4.66 [0.05] m/s; P < 0.001 compared with control) and in mice sedated with sodium pentobarbital (2.89 [0.17] m/s; P < 0.001 compared with control). In addition, cfPWV was pharmacologically modulated and measured in a longitudinal experiment with eNOS-/mice demonstrating the applicability of this technique. In conclusion, these results show that applanation tonometry is a powerful tool for the noninvasive assessment of cfPWV in mice. The technique is characterized by a high temporal resolution, reproducibility, and sensitivity, and the technical requirements are basic, thus aiding to a greater diffusion of arterial stiffness measurements in mouse models.

American journal of physiology. Heart and circulatory physiology, 2002

An increase in coronary perfusion, transversal stretch of the myocardium, increases developed for... more An increase in coronary perfusion, transversal stretch of the myocardium, increases developed force (F(dev)) (Gregg effect) through activation of stretch-activated ion channels (SACs). Lengthening of the muscle, longitudinal stretch of the myocardium, causes an immediate increase in F(dev) followed by a slow F(dev) increase (Anrep effect). In isometrically contracting perfused papillary muscles of Wistar rats, we investigated whether both effects were based on similar stretch-induced mechanisms by measuring F(dev) and intracellular Ca(2+) concentration ([Ca(2+)](i)) after a muscle length increase from 85% to 95% L(max) (length at which maximal isometric force develops) at low and high coronary perfusion before and after inhibition of SACs with gadolinium (10 micromol/l Gd(3+)). The increase of F(dev) and peak [Ca(2+)](i) by the Gregg effect was of similar magnitude as the Anrep effect (from 3.5 +/- 0.8 to 3.9 +/- 1.2 mN/mm(2) and from 3.0 +/- 0.7% to 3.8 +/- 0.9% normalized [Ca(2+)]...

Cardiovascular research, 2001

In mammalian cardiomyocytes, alpha isoforms of Na(+)/K(+) ATPase have specific localisation and f... more In mammalian cardiomyocytes, alpha isoforms of Na(+)/K(+) ATPase have specific localisation and function, but their role in endocardial endothelium is unknown. Different alpha isoforms in endocardial endothelium and cardiomyocytes of rabbit were investigated by measuring contractile parameters of papillary muscles, by RT-PCR, by Western blots and by immunocytochemistry. Inhibition of Na(+)/K(+) ATPase by decreasing external K(+) from 5.0 to 0.5 mmol/l caused biphasic inotropic effects. The maximal negative inotropic effect at external K(+) of 2.5 mmol/l was significantly larger in +EE muscles (with intact endocardial endothelium) than in -EE muscles (with endocardial endothelium removed) (-22.5+/-2.4% versus -5.9+/-4.0%, n=7, P<0.05). Further decrease of K(+) to 0.5 mmol/l caused endothelium-independent positive inotropy (27.8+/-11.8% for +EE versus 18.6+/-11.3% for -EE, n=7, P>0.05). Inhibition of Na(+)/K(+) ATPase either by dihydro-ouabain (10(-9) to 10(-4) mol/l, n=4) or by...

PLOS ONE, 2015

L-type Ca 2+ channel (VGCC) mediated Ca 2+ influx in vascular smooth muscle cells (VSMC) contribu... more L-type Ca 2+ channel (VGCC) mediated Ca 2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by α1adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (V m) of VSMC is not clear yet. Here, we show that α1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca 2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca 2+ release and the tonic contraction determined by Ca 2+ influx. The latter component involves both Ca 2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca 2+ influx by small variations of the VSMC V m causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by α1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca 2+ release from noncontractile sarcoplasmic reticulum Ca 2+ stores. Results of this study point to a complex interactions between α1-adrenoceptor-mediated VSMC contractile performance and Ca 2+ release form contractile or non-contractile Ca 2+ stores with concomitant Ca 2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein.

The American journal of physiology, 1995

The whole cell mode of the patch-clamp technique was applied to cultured endocardial endothelial ... more The whole cell mode of the patch-clamp technique was applied to cultured endocardial endothelial cells from the porcine right ventricle to study their electrophysiological properties. With isotonic pipette and bathing solutions (300-310 mosmol/kgH2O), single endocardial endothelial cells had resting membrane potentials ranging from -20 to -90 mV (mean = -55 +/- 20 mV, n = 48). In voltage-clamp experiments, the main membrane current was an inwardly rectifying K+ current with all characteristics described for the inwardly rectifying K+ current in vascular endothelium. Outward currents at positive clamp potentials were small, but when cell swelling was induced by means of a hypertonic pipette or hypotonic bathing solution and ATP (5 mM) was present in the pipette solution, a large outwardly rectifying current developed. This volume-activated current was insensitive to extracellular K+ or Na+ concentration variations but sensitive to changes in extracellular Cl- concentrations. It was i...

Thrombosis and Haemostasis, 2013

SummaryArterial ageing may be associated with a reduction in vasodilation due to increased reacti... more SummaryArterial ageing may be associated with a reduction in vasodilation due to increased reactive oxygen species (ROS) production, whereas endothelial cell activation induces procoagulant changes. However, little is known on the effect of ageing on expression of anticoagulant endothelial markers such as endothelial protein C receptor (EPCR). To study age-associated alterations in smooth muscle cell (SMC) and endothelial cell (EC) structure and function, the aorta was isolated from 10-week-and 12– and 24-month-old C57BL/6J mice and analysed for its expression of genes involved in senescence, oxidative stress production, coagulation and matrix remodelling. In addition, vasorelaxation experiments were performed using 10-week-and 24-month-old thoracic aortic ring segments in organ chamber baths. The media thickness of the thoracic aorta progressively increased with age, associated with hypertrophy of vascular SMCs. Basal nitric oxide production and sensitivity to acetylcholine-mediate...

Advances in Experimental Medicine and Biology, 2003

FJ&ure 1. Grow1h, performance and rhythmicity of lhe myocardium, lhe subneural plexus (SNP) and P... more FJ&ure 1. Grow1h, performance and rhythmicity of lhe myocardium, lhe subneural plexus (SNP) and Purkinje fibers can be affected by EE (EE) and endo1helium of myocardial capillaries (MyoCapE) via two palhways: autocrine-paracrine coupling (left) and/or blood-heart barrier (right). AI and All: angiotensin I and II, ACE: