Sébastien Foulquier

Cerebral small vessels feed and protect the brain parenchyma thanks to the unique features of the blood–brain barrier. Cerebrovascular dysfunction is therefore seen as a detrimental factor for the initiation of several central nervous system (CNS) disorders, such as stroke, cerebral small vessel disease (cSVD), and Alzheimer’s disease. The main working hypothesis linking cerebrovascular dysfunction to brain disorders includes the contribution of neuroinflammation. While our knowledge on… Show more

Cerebral small vessels feed and protect the brain parenchyma thanks to the unique features of the blood–brain barrier. Cerebrovascular dysfunction is therefore seen as a detrimental factor for the initiation of several central nervous system (CNS) disorders, such as stroke, cerebral small vessel disease (cSVD), and Alzheimer’s disease. The main working hypothesis linking cerebrovascular dysfunction to brain disorders includes the contribution of neuroinflammation. While our knowledge on microglia cells – the brain-resident immune cells – has been increasing in the last decades, the specific populations of microglia and macrophages surrounding brain vessels, vessel-associated microglia (VAM), and perivascular macrophages (PVMs), respectively, have been overlooked. This review aims to summarize the knowledge gathered on VAM and PVMs, to discuss existing knowledge gaps of importance for later studies and to summarize evidences for their contribution to cerebrovascular dysfunction. Show less

DOI 10.1038/s41440-019-0359-7

Our study demonstrates that the activation of MAS is important for microglia recruitment and vascular growth in the developing retina.

The causal relation between hypertension and cerebral small vessel disease (cSVD) remains elusive, and appropriate animal models are scarce. We aimed to assess the relevance of prolonged angiotensin II-induced hypertension in mice for the study of cSVD.
Adult male C57BL/6 mice were continuously infused for 3 months with Angiotensin II (Ang II; 2 μg/kg/min, sc) or saline (control) via osmotic minipumps. Blood pressure, neurological function, locomotor activity, and working memory (Y-maze… Show more

The causal relation between hypertension and cerebral small vessel disease (cSVD) remains elusive, and appropriate animal models are scarce. We aimed to assess the relevance of prolonged angiotensin II-induced hypertension in mice for the study of cSVD.
Adult male C57BL/6 mice were continuously infused for 3 months with Angiotensin II (Ang II; 2 μg/kg/min, sc) or saline (control) via osmotic minipumps. Blood pressure, neurological function, locomotor activity, and working memory (Y-maze alternation task) were assessed throughout the study. Short-term memory performance (object location task) was measured after 3 months of infusion. Blood–brain barrier (BBB) function was assessed by the presence of IgG leakage and quantified
in each brain area of interest. Microglial activation and myelin loss were studied in the areas of leakage.
Systolic blood pressure increased and remained elevated over the 3 months of Ang II infusion, while neurological scores and locomotor activity did not change. Working memory performance was also not changed, yet short-term memory performance was impaired in Ang II-treated mice compared to controls. While BBB leakages were present in both groups, mainly in the neocortex, hippocampus, and cerebral nuclei, Ang II-treated mice showed greater leakage than control mice, along with greater microglial density and soma size. Myelin loss was observed for the largest leaks.
Prolonged Ang II-induced hypertension is associated with large BBB leaks, microglial activation, myelin loss, and memory dysfunction in the absence of stroke. Show less

WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signalingmolecules.WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies
of heart and blood vessels. The high prevalence of these pathologies and their… Show more

WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signalingmolecules.WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies
of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and
the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is
addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After
highlighting the crosstalk between WNT, transforming growth factor-b and angiotensin II signaling, and
the emerging role ofWNTsignaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context. Show less

Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus… Show more

Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production. Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal-to-low diastolic blood pressure values. In contrast to dual RAS blockade, the add-on of AT2R stimulation does not exert significant blood pressure effects, but it may complement and enhance the anti-inflammatory and antifibrotic/de-stiffening effects of the AT1R blockade and improve the metabolic profile. Further studies will have to investigate these putative effects in particular for settings in which blood pressure reduction is not primarily desired. Show less

BACKGROUND AND PURPOSE:
Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation… Show more

BACKGROUND AND PURPOSE:
Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR.
METHODS:
Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY) and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships.
RESULTS:
Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA) 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR). Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR.
CONCLUSION:
In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values. Show less

BACKGROUND:
In the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease, all patients were at high cardiovascular risk, and a substantial proportion were hypertensive. We performed a post-hoc analysis to explore the hypothesis that telmisartan has a differential action in hypertensive vs. nonhypertensive patients.
METHODS:
The primary four-fold endpoint (composite of cardiovascular death, myocardial infarction (MI), stroke, or hospitalization… Show more

BACKGROUND:
In the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease, all patients were at high cardiovascular risk, and a substantial proportion were hypertensive. We performed a post-hoc analysis to explore the hypothesis that telmisartan has a differential action in hypertensive vs. nonhypertensive patients.
METHODS:
The primary four-fold endpoint (composite of cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure), the secondary three-fold endpoint (cardiovascular death, MI, and stroke), the individual components, new onset of left ventricular hypertrophy (LVH), and new onset of albuminuria were analyzed.
RESULTS:
There was no evidence for a significantly differential treatment effect of telmisartan in hypertensive and nonhypertensive patients for any endpoints, although the occurrence of the secondary three-fold endpoint was significantly lower in the telmisartan group (13.0%) compared with placebo (15.0%, P < 0.05) only in hypertensive patients. Moreover, data from this post-hoc analysis suggest that MI may be less frequent in hypertensive patients treated with telmisartan (3.8 vs. 5.1%; P < 0.05). Telmisartan may also reduce new onset of LVH (nonhypertensive patients P < 0.05; hypertensive patients P < 0.001) in both subgroups, and new onset of microalbuminuria and macroalbuminuria in hypertensive patients (P < 0.001 and P < 0.01, respectively).The effect of telmisartan in hypertensive and nonhypertensive patients at high cardiovascular risk was not different. This post-hoc analysis suggests that MI may be further reduced by telmisartan in hypertensive patients. Further investigations are needed to study the hypotheses raised by this explanatory analysis. Show less

The renin-angiotensin system (RAS) plays an important role in the initiation and progression of tissue injuries in the cardiovascular and nervous systems. The detrimental actions of the AT1 receptor (AT1R) in hypertension and vascular injury, myocardial infarction and brain ischemia are well established. In the past twenty years, protective actions of the RAS, not only in the cardiovascular, but also in the nervous system, have been demonstrated. The so-called protective arm of the RAS includes… Show more

The renin-angiotensin system (RAS) plays an important role in the initiation and progression of tissue injuries in the cardiovascular and nervous systems. The detrimental actions of the AT1 receptor (AT1R) in hypertension and vascular injury, myocardial infarction and brain ischemia are well established. In the past twenty years, protective actions of the RAS, not only in the cardiovascular, but also in the nervous system, have been demonstrated. The so-called protective arm of the RAS includes AT2-receptors and Mas receptors (AT2R and MasR) and is characterized by effects different from and often opposing those of the AT1R. These include anti-inflammation, anti-fibrosis, anti-apoptosis and neuroregeneration that can counterbalance pathological processes and enable recovery from disease. The recent development of novel, small-molecule AT2R agonists offers a therapeutic potential in humans with a variety of clinical indications. Show less

Foulquier S, Dupuis F, Perrin-Sarrado C, Maguin Gaté K, Leroy P, Liminana P, Atkinson J, Capdeville-Atkinson C, Lartaud I.

Short-term treatment with TELMI, but not with CANDE, reverses narrowing of pial arteriolar ID in SHR. This may involve PPAR-gamma related mechanisms, since CANDE+PIO treatment induced similar effects, and a better blockade of AT1
receptors.

Foulquier S, Steckelings UM, Unger T.
It is now widely accepted that the angiotensin AT(2) receptor (AT(2)R) plays an important protective role during pathophysiologic conditions, acting as a repair system. The development of the first selective nonpeptide AT(2)R agonist C21 accelerated our understanding of AT(2)R-mediated protective signaling and actions. This article reviews the impact of C21 on blood pressure in normotensive and hypertensive animal models. Although C21 does not act as a… Show more

Foulquier S, Steckelings UM, Unger T.
It is now widely accepted that the angiotensin AT(2) receptor (AT(2)R) plays an important protective role during pathophysiologic conditions, acting as a repair system. The development of the first selective nonpeptide AT(2)R agonist C21 accelerated our understanding of AT(2)R-mediated protective signaling and actions. This article reviews the impact of C21 on blood pressure in normotensive and hypertensive animal models. Although C21 does not act as a classical antihypertensive drug, it could be useful in preventing hypertension-induced vascular and other end organ damages via anti-apoptotic, anti-fibrotic and anti-inflammatory actions. In particular, a strong body of evidence started to emerge around its anti-inflammatory feature. This property should be further investigated for potential clinical indications in cardiovascular diseases and beyond. Show less

Foulquier S, Dupuis F, Perrin-Sarrado C, Maguin Gaté K, Merhi-Soussi F, Liminana P, Kwan YW, Capdeville-Atkinson C, Lartaud I, Atkinson J.
BACKGROUND:
Angiotensin II (Ang II) induces constriction (AT(1)) and dilation (AT(2) receptors) of cerebral arterioles. High sodium intake induces changes in receptors expression and loss of AT(2)-mediated vasodilation in extracerebral vessels. We investigated whether high salt modifies the AT(2)-mediated response of cerebral… Show more

Foulquier S, Dupuis F, Perrin-Sarrado C, Maguin Gaté K, Merhi-Soussi F, Liminana P, Kwan YW, Capdeville-Atkinson C, Lartaud I, Atkinson J.
BACKGROUND:
Angiotensin II (Ang II) induces constriction (AT(1)) and dilation (AT(2) receptors) of cerebral arterioles. High sodium intake induces changes in receptors expression and loss of AT(2)-mediated vasodilation in extracerebral vessels. We investigated whether high salt modifies the AT(2)-mediated response of cerebral arterioles.
METHODS:
Three-month-old male Wistar rats received drinking water supplemented or not with 1% NaCl. We measured at day 4 or 30 plasma aldosterone concentration, AT receptors expression (brain microvessels, western blot, RT-qPCR), internal diameter of pial arterioles (cranial window) following suffusion with Ang II (10(-6) mol/l, or 10(-8) mol/l + losartan 10(-5) mol/l), serotonin (5-HT, 10(-6) mol/l), sodium nitroprusside (10(-5) mol/l) and adenosine diphosphate (ADP, 10(-4) mol/l).
RESULTS:
High salt did not modify arterial pressure, baseline arteriolar diameter, vasoconstriction to Ang II or 5-HT, nor vasodilation to SNP. High salt lowered plasma aldosterone concentration (d4 138 ± 71 not significant vs. control 338 ± 73; d30 150 ± 21 P < 0.05 vs. control 517 ± 79 μmol/l). AT receptors mRNA did not change while protein level of AT(2) receptors decreased at d4 (64 ± 9% of control, P < 0.05). AT(2)-mediated vasodilation (control d4; d30 8 ± 2; 5 ± 2%) was abolished at d4 (-2 ± 2%, P < 0.05) and reversed to vasoconstriction at d30 (-7 ± 2%, P < 0.05). ADP-induced vasodilation is abolished at d30 (2 ± 2, P < 0.05 vs. control 19 ± 4%).
CONCLUSION:
High salt specifically abolishes AT(2)-mediated vasodilation, immediately, via decreased level of AT(2) receptor protein, and after 30 days, in association with abolition of endothelial vasodilation. Such loss of AT(2)-mediated vasodilation may be deleterious in case of stroke. Show less