Why Are Women Predisposed to Intracranial Aneurysm?

Intracranial aneurysm (IA) is a frequent and generally asymptomatic cerebrovascular abnormality characterized as a localized dilation and wall thinning of intracranial arteries that preferentially arises at the arterial bifurcations of the circle of Willis. The devastating complication of IA is its rupture, which results in subarachnoid hemorrhage that can lead to severe disability and death. IA affects about 3% of the general population with an average age for detection of rupture around 50 years.

Notch3 immunotherapy improves cerebrovascular responses in CADASIL mice.

Objective: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by dominant mutations in the NOTCH3 receptor, is the most aggressive small vessel disease of the brain. A key feature of its pathogenesis is accumulation of the extracellular domain of NOTCH3 receptor (Notch3 ) in small vessels, with formation of characteristic extracellular deposits termed granular osmiophilic material (GOM). Here, we investigated the therapeutic potential of a mouse monoclonal antibody (5E1) that specifically recognizes Notch3 .

Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis.

Abnormal activity of the renin-angiotensin-aldosterone system plays a causal role in the development of hypertension, atherosclerosis, and associated cardiovascular events such as myocardial infarction, stroke, and heart failure. As both a vasoconstrictor and a proinflammatory mediator, angiotensin II (Ang II) is considered a potential link between hypertension and atherosclerosis. However, a role for Ang II-induced inflammation in atherosclerosis has not been clearly established, and the molecular mechanisms and intracellular signaling pathways involved are not known.

Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries.

CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3 mouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels, as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone.

Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics.

Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor of metalloproteinase 3) accumulation in the vascular extracellular matrix in CADASIL is a key contributor to cerebrovascular dysfunction.

Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice.

Objective: CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3(ECD) ) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3(ECD) -containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes.

Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism.

Background And Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, the most common heritable small vessel disease of the brain, is caused by dominant mutations in the NOTCH3 receptor that stereotypically lead to age-dependent Notch3ECD deposition in the vessels. NOTCH3 loss of function has been demonstrated for few mutations. However, whether this finding applies to all mutations and whether a loss-of-function mechanism drives the manifestations of the disease remain yet unknown.

Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, one of the most common inherited small vessel diseases of the brain, is characterized by a progressive loss of vascular smooth muscle cells and extracellular matrix accumulation. The disease is caused by highly stereotyped mutations within the extracellular domain of the NOTCH3 receptor (Notch3(ECD)) that result in an odd number of cysteine residues. While CADASIL-associated NOTCH3 mutations differentially affect NOTCH3 receptor function and activity, they all are associated with early accumulation of Notch3(ECD)-containing aggregates in small vessels.

Transcriptome analysis for Notch3 target genes identifies Grip2 as a novel regulator of myogenic response in the cerebrovasculature.

Objective: Notch3 is critically important for the structure and myogenic response of distal arteries, particularly of cerebral arteries. However, signaling pathways acting downstream of Notch3 remain largely unknown.

Methods And Results: Transcriptome analysis using tail arteries of Notch3-null mice identified a core set of 17 novel Notch3-regulated genes confirmed in tail or brain arteries.

Notch signalling in smooth muscle cells during development and disease.

The Notch signalling pathway is a highly conserved cell-cell signalling mechanism that plays a central role in the development and maturation of most vertebrate organs. In vertebrates, Notch receptors, several ligands, and components of the downstream signalling machinery are expressed in the vessel. Over the past decade, numerous studies have highlighted the critical role of the Notch pathway in the vasculature.

Human serum albumin improves endothelial dysfunction and survival during experimental endotoxemia: concentration-dependent properties.

Objectives: The mechanisms by which human serum albumin might protect against sepsis-induced organ dysfunction and improve survival are not elucidated. The present study was designed to assess the effects of two concentrations of human serum albumin on endotoxin-induced mortality as well as on endothelial and organ dysfunctions in both mouse and cell models.

Design: Prospective, randomized, controlled experimental study.

Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries.

Blood flow reduction induces inward remodeling of resistance arteries (RAs). This remodeling occurs in ischemic diseases, diabetes and hypertension. Nonetheless, the effect of flow reduction per se, independent of the effect of pressure or metabolic influences, is not well understood in RA.

Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease.

Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model.

Role of angiotensin II in the remodeling induced by a chronic increase in flow in rat mesenteric resistance arteries.

Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown.

Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries.

Recombinant human activated protein C (rhAPC) is one of the treatment panels for improving vascular dysfunction in septic patients. In a previous study, we reported that rhAPC treatment in rat endotoxemia improved vascular reactivity, although the mechanisms involved are still under debate. In the present study, we hypothesized that rhAPC may improve arterial dysfunction through its nonanticoagulant properties.

Detrimental hemodynamic and inflammatory effects of microparticles originating from septic rats.

Objective: Microparticles (MPs) are membrane vesicles with procoagulant and proinflammatory properties released during cell activation and might be potentially involved in the pathophysiology of septic shock. This study was designed to assess the effects of MPs from septic origin on the systemic hemodynamics as well as on the inflammatory, oxidative, and nitrosative stresses.

Design: A prospective, randomized, controlled experimental study with repeated measurements.

Human serum albumin improves arterial dysfunction during early resuscitation in mouse endotoxic model via reduced oxidative and nitrosative stresses.

Human serum albumin (HSA) is used as a resuscitation fluid in sepsis. This study investigated the potential protective properties of HSA on vascular function in a mouse endotoxic model in terms of oxidative and nitrosative stresses. Swiss mice were treated with either lipopolysaccharide (LPS) (50 mg/kg i.

Effects of red wine polyphenols on postischemic neovascularization model in rats: low doses are proangiogenic, high doses anti-angiogenic.

Polyphenols, present in green tea, grapes, or red wine, have paradoxical properties: they protect against cardiac and cerebral ischemia but inhibit angiogenesis in vitro. So we investigated the effects of polyphenols in vivo on postischemic neovascularization. Rats treated with low (0.