Notch signaling in vascular smooth muscle cells is required to pattern the cerebral vasculature.
ABSTRACT: Stroke is the third leading cause of death and a significant contributor of morbidity in the United States. In humans, suboptimal cerebral collateral circulation within the circle of Willis (CW) predisposes to ischemia and stroke risk in the setting of occlusive carotid artery disease. Unique genes or developmental pathways responsible for proper CW formation are unknown. Herein we characterize a mouse model lacking Notch signaling in vascular smooth muscle cells (vSMCs), in which the animals are intolerant to reduced cerebral blood flow. Remarkably, unilateral carotid artery ligation results in profound neurological sequelae and death. After carotid ligation, perfusion of the ipsilateral cerebral hemisphere was markedly diminished, suggesting an anastomotic deficiency within the CW. High-resolution microcomputed tomographic (micro-CT) imaging revealed profound defects in cerebrovascular patterning, including interruption of the CW and anatomic deformity of the cerebral arteries. These data identify a vSMC-autonomous function for Notch signaling in patterning and collateral formation within the cerebral arterial circulation. The data further implicate genetic or functional deficiencies in Notch signaling in the pathogenesis of anatomic derangements underlying cerebrovascular accidents.
Project description:The circle of Willis (cW) is a major arterial collateral structure interconnecting hemispheric circulation within the brain, and in humans, anatomical variation of the cW is linked to stroke risk. Our prior studies on adult mice deficient in vascular smooth muscle cell (vSMC) Notch signaling revealed altered cerebroarterial maturation and patterning, including an anatomically incompetent cW similar to human variants. However, a developmental dependency on Notch signaling for cW formation in this model remained uncharacterized. Through temporospatial embryonic analyses, we now demonstrate that cW assembly is a pre-natal process highly sensitive to vSMC Notch signals, whose absence results in delayed nascent vascular plexus formation and under-development of the cW including the key anterior communicating artery (AComA) interconnecting anterior forebrain circulation. Mutant embryos additionally feature reduced vSMC coverage, non-uniform calibers and asymmetric branching at bifurcations of the major proximal cerebral arteries. At the cellular level, a notable reduction in vascular endothelial cell proliferation exists in the region of AComA assembly despite the presence of Vegfa. Furthermore, Notch signaling-deficient vSMCs in developing cerebral vessels feature reduced Pdgfr? and Jagged1 levels and impaired proliferation. These collective findings in the embryonic brain support studies in adult animals demonstrating a reliance on intact vSMC Notch signaling for optimal neovascular responses to angiogenic stimuli. Importantly, the new data provide unique insights into the native formation of the cW and underscore a pioneering developmental role for vSMC Notch signaling in regulating temporospatial assembly of the clinically relevant cW.
Project description:We report on oxygenation changes noninvasively recorded by multichannel continuous-wave near infrared spectroscopy (CW-NIRS) during endovascular neuroradiologic interventions requiring temporary balloon occlusion of arteries supplying the cerebral circulation. Digital subtraction angiography (DSA) provides reference data on the site, timing, and effectiveness of the flow stagnation as well as on the amount and direction of collateral circulation. This setting allows us to relate CW-NIRS findings to brain specific perfusion changes. We focused our analysis on the transition from normal perfusion to vessel occlusion, i.e., before hypoxia becomes clinically apparent. The localization of the maximal response correlated either with the core (occlusion of the middle cerebral artery) or with the watershed areas (occlusion of the internal carotid artery) of the respective vascular territories. In one patient with clinically and angiographically confirmed insufficient collateral flow during carotid artery occlusion, the total hemoglobin concentration became significantly asymmetric, with decreased values in the ipsilateral watershed area and contralaterally increased values. Multichannel CW-NIRS monitoring might serve as an objective and early predictive marker of critical perfusion changes during interventions-to prevent hypoxic damage of the brain. It also might provide valuable human reference data on oxygenation changes as they typically occur during acute stroke.
Project description:Collateral blood flow plays a pivotal role in steno-occlusive internal carotid artery (ICA) disease to prevent irreversible ischaemic damage. Our aim was to investigate the effect of carotid artery disease upon cerebral perfusion and cerebrovascular reactivity and whether haemodynamic impairment is influenced at brain tissue level by the existence of primary and/or secondary collateral. Eighty-eight patients with steno-occlusive ICA disease and 29 healthy controls underwent MR examination. The presence of collaterals was determined with time-of-flight, two-dimensional phase contrast MRA and territorial arterial spin labeling (ASL) imaging. Cerebral blood flow and cerebrovascular reactivity were assessed with ASL before and after acetazolamide. Cerebral haemodynamics were normal in asymptomatic ICA stenosis patients, as opposed to patients with ICA occlusion, in whom the haemodynamics in both hemispheres were compromised. Haemodynamic impairment in the affected brain region was always present in symptomatic patients. The degree of collateral blood flow was inversely correlated with haemodynamic impairment. Recruitment of secondary collaterals only occurred in symptomatic ICA occlusion patients. In conclusion, both CBF and cerebrovascular reactivity were found to be reduced in symptomatic patients with steno-occlusive ICA disease. The presence of collateral flow is associated with further haemodynamic impairment. Recruitment of secondary collaterals is associated with severe haemodynamic impairment.
Project description:We present the first case report of coronary-carotid artery collateral formation in Takayasu's arteritis. There was a vasculitic involvement of both subclavian and carotid arteries with critical stenosis; cerebral perfusion was supported with collaterals arising from the mesenteric arteries and coronary artery. <Learning objective: A case of coronary-carotid artery collateral formation in Takayasu's arteritis is presented. Such an angiographic finding has not been reported previously, and this case could be the first description of coronary-carotid artery collaterals development. The learning objective of the article is to evaluate collateral circulation in Takayasu's arteritis from different vasculature including the coronary system.>.
Project description:The density of native (preexisting) collaterals varies widely and is a significant determinant of variation in severity of stroke, myocardial infarction, and peripheral artery disease. However, little is known about mechanisms responsible for formation of the collateral circulation in healthy tissues.We previously found that variation in vascular endothelial growth factor (VEGF) expression causes differences in collateral density of newborn and adult mice. Herein, we sought to determine mechanisms of collaterogenesis in the embryo and the role of VEGF in this process.Pial collaterals begin forming between embryonic day 13.5 and 14.5 as sprout-like extensions from arterioles of existing cerebral artery trees. Global VEGF-A overexpressing mice (Vegf(hi/+)) formed more, and Vegf(lo/+) formed fewer, collaterals during embryogenesis, in association with differences in vascular patterning. Conditional global reduction of Vegf or Flk1 only during collaterogenesis significantly reduced collateral formation, but now without affecting vascular patterning, and the effects remained in adulthood. Endothelial-specific Vegf reduction had no effect on collaterogenesis. Endothelial-specific reduction of a disintegrin-and-metalloprotease-domain-10 (Adam10) and inhibition of ?-secretase increased collateral formation, consistent with their roles in VEGF-induced Notch1 activation and suppression of prosprouting signals. Endothelial-specific knockdown of Adam17 reduced collateral formation, consistent with its roles in endothelial cell migration and embryonic vascular stabilization, but not in activation of ligand-bound Notch1. These effects also remained in adulthood.Formation of pial collaterals occurs during a narrow developmental window via a sprouting angiogenesis-like mechanism, requires paracrine VEGF stimulation of fetal liver kinase 1-Notch signaling, and adult collateral number is dependent on embryonic collaterogenesis.
Project description:Congenital absence of the internal carotid artery is a rare occurrence. Even more infrequent are cases where the patient has a bilateral absence of the internal carotid arteries. Reported is a case of a 52-year-old woman who presented with optic nerve neuropathy, and was incidentally discovered to have a congenital bilateral absence of her internal carotid arteries. During computed tomography angiography imaging looking for cerebral venous thrombosis, related to her preexisting condition of bilateral elevated optic discs and residual left optic neuropathy, the findings were made. The absence of the arteries is not always recognizably symptomatic, with most findings being incidental through imaging studies only. This is because collateral flow allows for sufficient cerebral circulation. However, this condition puts such patients at higher risk for conditions such as aneurysms and subsequently strokes where the collateral flow exists.
Project description:BACKGROUND AND PURPOSE:External counterpulsation improves cerebral perfusion velocity in acute stroke and may stimulate collateral artery growth. However, whether (non-acute) at-risk patients with high-grade carotid artery disease may benefit from counterpulsation needs to be validated. METHODS:Twenty-eight patients (71 ± 6.5 years, five women) with asymptomatic unilateral chronic severe internal carotid artery stenosis (>70%) or occlusion were randomized to receive 20 min active counterpulsation followed by sham treatment or vice versa. Cerebral blood flow velocity (CBFV) (measured bilaterally by transcranial middle cerebral artery Doppler), tissue oxygenation index (TOI) (measured over the bilateral prefrontal cortex by near-infrared spectroscopy) and cerebral hemodynamic parameters, such as relative pulse slope index (RPSI), were monitored. RESULTS:Ipsilateral mean CBFV (?Vmean +3.5 ± 1.2 cm/s) and tissue oxygenation (?TOI +2.86 ± 0.8) increased significantly during active counterpulsation compared to baseline, whilst the sham had little effect (?Vmean +1.13 ± 1.1 cm/s; ?TOI +1.25 ± 0.65). On contralateral sides, neither counterpulsation nor sham control had any effect on either parameter. During counterpulsation, early dynamic changes in ?RPSI of the ipsilateral CBFV signal predicted improved tissue oxygenation during counterpulsation (odds ratio 1.179, 95% confidence interval 1.01-1.51), whilst baseline cerebrovascular reactivity to hypercapnia failed to show an association. CONCLUSIONS:In patients with high-grade carotid disease, ipsilateral cerebral oxygenation and blood flow velocity are increased by counterpulsation. This is a necessary condition for the stimulation of regenerative collateral artery growth and thus a therapeutic concept for the prevention of cerebral ischaemia. This study provides a rationale for further clinical investigations on the long-term effects of counterpulsation on cerebral hemodynamics and collateral growth.
Project description:BACKGROUND Acute cerebral infarction is a major clinical subtype of ischemic stroke that has become a leading cause of death and disability worldwide. Aldehyde dehydrogenase 2 (ALDH2) is an important oxidative enzyme in alcohol metabolism. The polymorphism of ALDH2 Glu504Lys polymorphism modifies the activity of this enzyme. However, the potential association between the allelic variation of ALDH2 Glu504Lys with collateral circulation and short-term prognosis of acute cerebral infarction remains unclear. MATERIAL AND METHODS A total of 394 patients with acute cerebral infarction were recruited for ALDH2 genotyping using direct sequencing. Cerebrovascular stenosis and collateral circulation were evaluated by digital subtraction angiography (DSA). Short-term prognosis was assessed in accordance with the modified Ranking Scale (mRS). RESULTS We identified 297 as EAS and 394 as IAS. There were more patients with occluded blood vessel in the opened group and far fewer in the unopened group. ALDH2 polymorphism was significantly different among the primary, secondary, and tertiary opened groups. ALDH2 gene Glu504Lys was significantly associated with short-term prognosis. The genotype GA+AA of ALDH2 gene Glu504Lys locus was an independent risk factor of poor 90-day prognosis. CONCLUSIONS ALDH2 Glu504Lys could be a risk factor for collateral circulation and a negative predictor for short-term prognosis in acute cerebral infarction in Han Chinese. ALDH2 Glu504Lys could be a new therapeutic target for patients with acute cerebral infarction.
Project description:The presence of a native collateral circulation in tissues lessens injury in occlusive vascular diseases. However, differences in genetic background cause wide variation in collateral number and diameter in mice, resulting in large variation in protection. Indirect estimates of collateral perfusion suggest that wide variation also exists in humans. Unfortunately, methods used to obtain these estimates are invasive and not widely available. We sought to determine whether differences in genetic background in mice result in variation in branch patterning of the retinal arterial circulation, and whether these differences predict strain-dependent differences in pial collateral extent and severity of ischemic stroke. Retinal patterning metrics, collateral extent, and infarct volume were obtained for 10 strains known to differ widely in collateral extent. Multivariate regression was conducted, and model performance was assessed using K-fold cross-validation. Twenty-one metrics varied with strain (p<0.01). Ten metrics (e.g., bifurcation angle, lacunarity, optimality) predicted collateral number and diameter across seven regression models, with the best model closely predicting (p<0.0001) number (±1.2-3.4 collaterals, K-fold R2=0.83-0.98), diameter (±1.2-1.9 ?m, R2=0.73-0.88), and infarct volume (±5.1 mm3, R2=0.85-0.87). An analogous set of the most predictive metrics, obtained for the middle cerebral artery (MCA) tree in a subset of the above strains, also predicted (p<0.0001) collateral number (±3.3 collaterals, K-fold R2=0.78) and diameter (±1.6 ?m, R2=0.86). Thus, differences in arterial branch patterning in the retina and the MCA trees are specified by genetic background and predict variation in collateral extent and stroke severity. If also true in human, and since genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar "retinal predictor index" could serve as a non- or minimally invasive biomarker for collateral extent in brain and other tissues. This could aid prediction of severity of tissue injury in the event of an occlusive event or development of obstructive disease and in patient stratification for treatment options and clinical studies.
Project description:The cerebral circulation is unique in its ability to maintain blood flow to the brain under widely varying physiologic conditions. Incorporating this autoregulatory response is necessary for cerebral blood flow (CBF) modeling, as well as investigations into pathological conditions. We discuss a one-dimensional (1D) nonlinear model of blood flow in the cerebral arteries coupled to autoregulatory lumped-parameter (LP) networks. The LP networks incorporate intracranial pressure (ICP), cerebrospinal fluid (CSF), and cortical collateral blood flow models. The overall model is used to evaluate changes in CBF due to occlusions in the middle cerebral artery (MCA) and common carotid artery (CCA). Velocity waveforms at the CCA and internal carotid artery (ICA) were examined prior and post MCA occlusion. Evident waveform changes due to the occlusion were observed, providing insight into cerebral vasospasm monitoring by morphological changes of the velocity or pressure waveforms. The role of modeling of collateral blood flows through cortical pathways and communicating arteries was also studied. When the MCA was occluded, the cortical collateral flow had an important compensatory role, whereas the communicating arteries in the circle of Willis (CoW) became more important when the CCA was occluded. To validate the model, simulations were conducted to reproduce a clinical test to assess dynamic autoregulatory function, and results demonstrated agreement with published measurements.