Embryological development of the human cranio-facial arterial system: a pictorial review.

The embryological development of the cerebral vasculature is very complex. Historical and also more recent studies based on human embryos, comparative anatomy and cerebral angiographies allowed us to better understand this vasculature development. The knowledge and understanding of such embryological development are important for physicians interested in neurovascular pathologies. Indeed, all vascular variants and almost all vascular pathologies, such as aneurysms, dolichoectasia, atherosclerosis, and neurovascular conflicts could be explained by an alteration during the embryological life. There are also many variants of these vascular structures present in normal developed adults, which are variably associated with pathological entities. Understanding the process which leads to the development of the normal cerebral arterial system in humans is, therefore, very important to have a better knowledge of the possible clinical and surgical implications of these anomalies. In this paper, we review the embryological development of the cranio-facial arterial vasculature from its beginning at approximately days 21-50 of intrauterine life, with pictures illustrating each developmental phase.

Prevalence and Clinical Implications of the Primitive Trigeminal Artery and its Variants: A Meta-Analysis.

BACKGROUND: The primitive trigeminal artery (PTA) is the most common and the largest persistent carotid-basilar anastomosis. Primitive trigeminal artery variants (PTAVs) are anastomoses between the internal carotid artery and cerebellar arteries. These vessels pose a risk of hemorrhagic or ischemic complications during neurosurgical procedures in the parasellar and intrasellar regions. The aim of this study was to determine the prevalence of both PTA and PTAVs and their clinically important anatomic features. METHODS: Major electronic databases were thoroughly searched for studies on PTA and PTAV. References in the included articles were also evaluated. Data regarding prevalence, laterality, origin, course patterns, and associated anomalies were extracted and pooled into a meta-analysis. RESULTS: A total of 39 studies (110,866 patients) were included in the meta-analysis. The total pooled prevalence estimate of PTA and PTAVs combined was 0.4% (95% confidence interval [CI], 0.3-0.5). Individually, PTA was present in 0.3% of patients and PTAV in 0.2%. Both arteries most often originated from the C4 internal carotid artery and took a course lateral to the dorsum sellae. The anterior inferior cerebellar artery type was the predominant PTAV (72.1%). Basilar artery hypoplasia was found in 42.5% of patients with a PTA. CONCLUSIONS: PTA and PTAVs are rare vessels, but they are clinically important because they can contribute to trigeminal neuralgia. Knowledge of the potential course of these arteries is essential in neuroradiology and neurosurgery, especially in minimally invasive procedures such as the endoscopic endonasal transsphenoidal approach to the pituitary gland and the percutaneous gasserian ganglion procedure.

Proteomic Analysis of Baboon Cerebral Artery Reveals Potential Pathways of Damage by Prenatal Alcohol Exposure.

Alcohol is one of the most widely misused substances in the world. Alcohol consumption by pregnant women often results in an array of fetal developmental abnormalities, but the damage to the fetus by alcohol remains poorly understood. The limited knowledge regarding the molecular targets of alcohol in the developing fetus constitutes one of the major obstacles in developing effective pharmacological interventions that could prevent fetal damage after alcohol consumption by pregnant women. The fetal cerebral artery is emerging as an important mediator of fetal cerebral damage by maternal alcohol drinking. In the present work, we conduct proteomics analysis of cerebral (basilar) artery lysates of near-term fetal baboons to search for protein targets of fetal alcohol exposure. Our study demonstrates that 3 episodes of binge alcohol exposure during the second trimester-equivalent of human pregnancy are sufficient to render profound changes in fetal cerebral artery proteome. These changes persisted, as they were detected in near-term fetuses. In particular, the relative abundance of 238 proteins differed significantly between control and alcohol-exposed fetuses. Enrichment analysis pointed at the group of metabolic activity proteins as a major class targeted by alcohol. Western blotting confirmed upregulation of the aldehyde dehydrogenase 6 family member A1 (ALDH6A1) in cerebral artery lysates from alcohol-exposed fetuses. This upregulation translated to greater ALDH activity of cerebral artery lysate of near-term fetuses following prenatal alcohol exposure when compared with controls.

Fetal Cerebrovascular Maturation: Effects of Hypoxia.

The human cerebral vasculature originates in the fourth week of gestation and continues to expand and diversify well into the first few years of postnatal life. A key feature of this growth is smooth muscle differentiation, whereby smooth muscle cells within cerebral arteries transform from migratory to proliferative to synthetic and finally to contractile phenotypes. These phenotypic transformations can be reversed by pathophysiological perturbations such as hypoxia, which causes loss of contractile capacity in immature cerebral arteries. In turn, loss of contractility affects all whole-brain cerebrovascular responses, including those involved in flow-metabolism coupling, vasodilatory responses to acute hypoxia and hypercapnia, cerebral autoregulation, and reactivity to activation of perivascular nerves. Future strategies to minimize cerebral injury following hypoxia-ischemic insults in the immature brain might benefit by targeting treatments to preserve and promote contractile differentiation in the fetal cerebrovasculature. This could potentially be achieved through inhibition of receptor tyrosine kinase-mediated growth factors, such as vascular endothelial growth factor and platelet-derived growth factor, which are mobilized by hypoxic and ischemic injury and which facilitate contractile dedifferentiation. Interruption of the effects of other vascular mitogens, such as endothelin and angiotensin-II, and even some miRNA species, also could be beneficial. Future experimental work that addresses these possibilities offers promise to improve current clinical management of neonates who have suffered and survived hypoxic, ischemic, asphyxic, or inflammatory cerebrovascular insults.

Characterization of Endothelial Cilia Distribution During Cerebral-Vascular Development in Zebrafish ( Danio rerio).

Objective- Endothelial cells (ECs) sense and respond to flow-induced mechanical stress, in part, via microtubule-based projections called primary cilia. However, many critical steps during vascular morphogenesis occur independent of flow. The involvement of cilia in regulating these stages of cranial vascular morphogenesis is poorly understood because cilia have not been visualized in primary head vessels. The objective of this study was to investigate involvement of cilia in regulating the early stages of cranial vascular morphogenesis. Approach and Results- Using high-resolution imaging of the Tg(kdrl:mCherry-CAAX) y171 ;(bactin::Arl13b:GFP) zebrafish line, we showed that cilia are enriched in the earliest formed cranial vessels that assemble via vasculogenesis and in angiogenic hindbrain capillaries. Cilia were more prevalent around the boundaries of putative intravascular spaces in primary and angiogenic vessels. Loss of cardiac contractility and blood flow, because of knockdown of cardiac troponin T type 2a ( tnnt2a) expression, did not affect the distribution of cilia in primary head vasculature. In later stages of development, cilia were detected in retinal vasculature, areas of high curvature, vessel bifurcation points, and during vessel anastomosis. Loss of genes crucial for cilia biogenesis ( ift172 and ift81) induced intracerebral hemorrhages in an EC-autonomous manner. Exposure to high shear stress induced premature cilia disassembly in brain ECs and was associated with intracerebral hemorrhages. Conclusions- Our study suggests a functional role for cilia in brain ECs, which is associated with the emergence and remodeling of the primary cranial vasculature. This cilia function is flow-independent, and cilia in ECs are required for cerebral-vascular stability.

Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1.

In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to endothelin-1 (ET-1), a potent vascular contractant and mitogen. In fetal lambs, chronic hypoxia (3,820-m altitude for the last 110 days of gestation) had no significant effect on plasma ET-1 levels or ETA receptor density in cerebral arteries but enhanced contractile responses to ET-1 in an ETA-dependent manner. In organ culture (24 h), 10 nM ET-1 increased medial thicknesses less in hypoxic than in normoxic arteries, and these increases were ablated by inhibition of PKC (chelerythrine) in both normoxic and hypoxic arteries but were attenuated by inhibition of CaMKII (KN93) and p38 (SB203580) in normoxic but not hypoxic arteries. As indicated by Ki-67 immunostaining, ET-1 increased medial thicknesses via hypertrophy. Measurements of colocalization between MLCK and SMαA revealed that organ culture with ET-1 also promoted contractile dedifferentiation in normoxic, but not hypoxic, arteries through mechanisms attenuated by inhibitors of PKC, CaMKII, and p38. These results support the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to ET-1 through pathways dependent upon PKC, CaMKII, and p38 that cause increased ET-1-mediated contractility, decreased ET-1-mediated smooth muscle hypertrophy, and a depressed ability of ET-1 to promote contractile dedifferentiation.

Maternal alcohol exposure during mid-pregnancy dilates fetal cerebral arteries via endocannabinoid receptors.

Prenatal alcohol exposure often results in fetal alcohol syndrome and fetal alcohol spectrum disorders. Mechanisms of fetal brain damage by alcohol remain unclear. We used baboons (Papio spp.) to study alcohol-driven changes in the fetal cerebral artery endocannabinoid system. Pregnant baboons were subjected to binge alcohol exposure via gastric infusion three times during a period equivalent to the second trimester of human pregnancy. A control group was infused with orange-flavored drink that was isocaloric to the alcohol-containing solution. Cesarean sections were performed at a time equivalent to the end of the second trimester of human pregnancy. Fetal cerebral arteries were harvested and subjected to in vitro pressurization followed by pharmacological profiling. During each alcohol-infusion episode, maternal blood alcohol concentrations (BAC) reached 80 mg/dL, that is, equivalent to the BAC considered legal intoxication in humans. Circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) remained unchanged. Ultrasound studies on pregnant mothers revealed that fetal alcohol exposure decreased peak systolic blood velocity in middle cerebral arteries when compared to pre-alcohol levels. Moreover, ethanol-induced dilation was observed in fetal cerebral arteries pressurized in vitro. This dilation was abolished by the mixture of AM251 and AM630, which block cannabinoid receptors 1 and 2, respectively. In the presence of AM251, the cannabinoid receptor agonist AEA evoked a higher, concentration-dependent dilation of cerebral arteries from alcohol-exposed fetuses. The difference in AEA-induced cerebral artery dilation vanished in the presence of AM630. CB1 and CB2 receptor mRNA and protein levels were similar in cerebral arteries from alcohol-exposed and control-exposed fetuses. In summary, alcohol exposure dilates fetal cerebral arteries via endocannabinoid receptors and results in an increased function of CB2.

Cognitive Functioning and Academic Achievement in Children Aged 6-8 Years, Born at Term After Intrauterine Growth Restriction and Fetal Cerebral Redistribution.

Objective: To determine whether cerebroplacental ratio, an indicator of fetal cerebral redistribution (FCR), predicts adverse results for neurodevelopment in intrauterine growth restriction (IUGR) infants. Methods: In a cohort of 5,702 infants, 64 were IUGR born at term with FCR. Five were excluded. Of the remainder, 32 presented an abnormal cerebroplacental ratio (IUGR-A) and 27 a normal one (IUGR-B). The controls were 61 appropriate-for-gestational-age children. Cognitive and academic outcomes and the odds ratio of lower academic scores were assessed by multivariate analysis of covariance and logistic regression. Results: IUGR-A children presented deficits in cognitive functioning and academic achievement in all domains. IUGR-B children presented slight deficits. Suboptimal cognitive functioning in IUGR-A was more marked in working memory. Abnormal cerebroplacental ratio predicted low academic scores in IUGR-A. Conclusions: FCR is a risk factor for IUGR infants, and cerebroplacental ratio identifies those most severely affected. Intervention programs may produce benefits in early-middle childhood.

Comparison of cerebral artery angle in adults and fetuses / Comparación del ángulo de arteria cerebral en adultos y fetos

In this study we generated casting specimens of human cerebral blood vessels for twenty-five fetuses and thirty-six adults. The degrees of the angles were measured and comprised for those blood vessels frequently involved in the interventional catheterization.

En este estudio generamos muestras de los vasos sanguíneos cerebrales humanos en veinticinco fetos y treinta y seis adultos. Fueron medidos y comprendidos los ángulos de aquellos vasos sanguíneos implicados frecuentemente en intervenciones de cateterismo.

Normal Doppler Reference Values of the Pericallosal Artery.

PURPOSE: To provide the normal reference values of the Doppler flow of the pericallosal artery in relation to gestational age from 18 to 41 weeks of gestation. MATERIALS AND METHODS: The pericallosal artery (PCA) was studied in 466 normal pregnancies. The pulsed Doppler evaluation of the pericallosal artery was done in A3 and A4 segments, and records from PI, RI and Vmax were studied. RESULTS: The resistance index of the pericallosal artery in A3/A4 segments exhibits a plateau from 18 to 31 weeks of gestation. After 31 weeks, a marked decrease becomes apparent. The pulsatility index of the pericallosal artery in A3/A4 segments shows a plateau until 36 weeks of gestation. During the final weeks of gestation, there is a decrease in the pulsatility index. Vmax exhibits a plateau for the maximal flow velocity in A3/A4 segments of the pericallosal artery from 18 to 28 weeks of gestation. After 28 weeks of gestation, there is a slight increase in Vmax. CONCLUSION: Normal reference values of the pericallosal artery might have an impact on clinical judgment during adaptive hemodynamic changes and regarding the progression of the fetal deterioration occurring in the presence of fetal hypoxia.

Quantitative comparison of cerebral artery development in human embryos with other eutherians.

The embryonic and early fetal human brain is known to undergo extraordinary expansion of its cellular population during embryonic and early fetal life, and is critically dependant on a steady supply of nutrients and oxygen for proper brain development. Quantitative analysis of the internal radius of the aorta and cerebral arteries in a range of eutherian mammals has been used to compare arterial flow to the developing human brain with that to the brains of non-human eutherians. Human embryos showed a much steeper rise of internal radius of the aorta with increasing body size than the embryos of non-human eutherians, but the thickness of the aorta rose at the same pace relative to body size in both humans and non-humans, suggesting that aortic pressure is similar in all eutherian embryos of a similar size. The sums of internal radii of both the internal carotids and vertebral arteries of human embryos raised to the fourth power were much lower at embryonic stages (less than 22 mm body length) than in non-human eutherians, were similar between humans and non-humans at 22-30 mm body length, and exceeded the non-humans at body lengths of more than 30 mm. The relative size of the internal calibre of the cerebral feeder arteries (internal carotid and vertebral) to the aorta did not change between embryonic and fetal sizes in either humans or non-humans. The findings suggest that the developing human brain may actually receive less blood flow at embryonic sizes (less than 22 mm body length) than do other mammalian embryos of a similar body size, but that internal carotid and vertebral flow is higher in human fetuses (body length greater than 30 mm) than in developing non-humans of the same body size. Increased flow to the developing human brain relative to non-humans is achieved by simultaneous increases in both aortic and cerebral feeder artery internal calibre.

Estimation of the growth rate in fetuses with an abnormal cerebroplacental ratio compared to those with suspected growth restriction without evidence of centralization of blood flow.

OBJECTIVES: To evaluate the growth rate in fetuses with suspected growth restriction according to their Doppler characteristics. METHODS: A retrospective cohort of fetuses with suspected growth restriction was identified. We reviewed umbilical artery and middle cerebral Doppler pulsatility indices and calculated the cerebroplacental ratio. Three study groups were determined: (1) normal umbilical artery Doppler findings; (2) abnormal umbilical artery findings with a normal cerebroplacental ratio; and (3) abnormal umbilical artery findings with an abnormal cerebroplacental ratio. The primary outcome was the growth rate as estimated by fetal biometry from serial sonographic evaluations. Analysis of the mean growth rate in each study group was performed by analysis of variance. In addition, linear regression analysis comparing the cerebroplacental ratio to the growth rate was performed. RESULTS: Fetal growth restriction was suspected in 416 patients; 176 patients were included in this analysis: 113, 38, and 25 in groups 1, 2, and 3 respectively. The estimated mean (SD) growth rate in group 3 was significantly lower than in groups 1 and 2: 8.3 (4.4) versus 19.6 (6.0) and 18.6 (7.7) g/d, respectively (P < .001). Linear regression analysis revealed a strong correlation between the growth rate and cerebroplacental ratio (r = 0.76; R(2) = 0.58) as well as the birth weight and cerebroplacental ratio (r = 0.78; R(2) = 0.61). CONCLUSIONS: In fetuses with suspected growth restriction and abnormal umbilical artery Doppler findings, an abnormal cerebroplacental ratio is strongly associated with reduced fetal growth. In contrast, if the cerebroplacental ratio is normal, even in the setting of abnormal umbilical artery Doppler findings, fetuses grow similarly to those with normal umbilical artery findings.

Cervical condition and fetal cerebral Doppler as determinants of adverse perinatal outcome after labor induction for late-onset small-for-gestational-age fetuses.

OBJECTIVE: To estimate the combined value of fetal cerebral Doppler examination and Bishop score for predicting perinatal outcome after labor induction for small-for-gestational-age (SGA) fetuses in the presence of normal umbilical artery Doppler recordings. METHODS: We conducted a cohort study in two tertiary centers, including 164 women with normal umbilical artery Doppler recordings who underwent induction of labor because of an estimated fetal weight < 10(th) percentile. The fetal middle cerebral artery pulsatility index and cerebroplacental ratio (CPR) were obtained in all cases within 24 h before induction. Cervical condition was assessed at admission using the Bishop score. A predictive model for perinatal outcomes was constructed using a decision-tree analysis algorithm. RESULTS: Both a very unfavorable cervix, defined as a Bishop score < 2, (odds ratio (OR), 3.18; 95% CI, 1.28-7.86) and an abnormal CPR (OR, 2.54; 95% CI, 1.18-5.61) were associated with an increased likelihood of emergency Cesarean section for fetal distress, but only the latter was significantly associated with the need for neonatal admission (OR, 2.43; 95% CI, 1.28-4.59). In the decision-tree analysis, both criteria significantly predicted the likelihood of Cesarean section for fetal distress. CONCLUSION: Combined use of the Bishop score and CPR improves the ability to predict overall Cesarean section (for any indication), emergency Cesarean section for fetal distress, and neonatal admission after labor induction for late-onset SGA in the presence of normal umbilical artery Doppler recordings.

The fetal cerebral circulation: three decades of exploration by the LLU Center for Perinatal Biology.

For more than three decades, research programs in the Center of Perinatal Biology have focused on the vascular biology of the fetal cerebral circulation. In the 1980s, research in the Center demonstrated that cerebral autoregulation operated over a narrower pressure range, and was more vulnerable to insults, in fetuses than in adults. Other studies were among the first to establish that compared to adult cerebral arteries, fetal cerebral arteries were more hydrated, contained smaller smooth muscle cells and less connective tissue, and had endothelium less capable of producing NO. Work in the 1990s revealed that pregnancy depressed reactivity to NO in extra-cerebral arteries, but elevated it in cerebral arteries through effects involving changes in cGMP metabolism. Comparative studies verified that fetal lamb cerebral arteries were an excellent model for cerebral arteries from human infants. Biochemical studies demonstrated that cGMP metabolism was dramatically upregulated, but that contraction was far more dependent on calcium influx, in fetal compared to adult cerebral arteries. Further studies established that chronic hypoxia accelerates functional maturation of fetal cerebral arteries, as indicated by increased contractile responses to adrenergic agonists and perivascular adrenergic nerves. In the 2000s, studies of signal transduction established age-dependent roles for PKG, PKC, PKA, ERK, ODC, IP3, myofilament calcium sensitivity, and many other mechanisms. These diverse studies clearly demonstrated that fetal cerebral arteries were functionally quite distinct compared to adult cerebral arteries. In the current decade, research in the Center has expanded to a more molecular focus on epigenetic mechanisms and their role in fetal vascular adaptation to chronic hypoxia, maternal drug abuse, and nutrient deprivation. Overall, the past three decades have transformed thinking about, and understanding of, the fetal cerebral circulation due in no small part to the sustained research efforts by faculty and staff in the Center for Perinatal Biology.

Cerebral angiogenesis during development: who is conducting the orchestra?

Blood vessels provide the brain with the oxygen and the nutrients it requires to develop and function. Endothelial cells (ECs) are the principal cell type forming the vascular system and driving its development and remodeling. All vessels are lined by a single EC layer. Larger blood vessels are additionally enveloped by vascular smooth muscle cells (VSMCs) and pericytes, which increase their stability and regulate their perfusion and form the blood-brain barrier (BBB). The development of the vascular system occurs by two processes: (1) vasculogenesis, the de novo assembly of the first blood vessels, and (2) angiogenesis, the creation of new blood vessels from preexisting ones by sprouting from or by division of the original vessel. The walls of maturing vessels produce a basal lamina and recruit pericytes and vascular smooth muscle cells for structural support. Whereas the process of vasculogenesis seems to be genetically programmed, angiogenesis is induced mainly by hypoxia in development and disease. Both processes and the subsequent vessel maturation are further orchestrated by a complex interplay of inhibiting and stimulating growth factors and their respective receptors, many of which are hypoxia-inducible. This chapter intends to give an overview about the array of factors directing the development and maintenance of the brain vasculature and their interdependent actions.

Neurodevelopmental outcome of 31 patients with borderline fetal ventriculomegaly.

AIM: We present the neurodevelopmental outcome of patients with isolated borderline fetal ventriculomegaly. METHODS: The present study was carried out at the Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University in July-December 2010. Prenatal second trimester detailed ultrasound examinations were performed by obstetricians at the Prenatal Diagnosis Department of Istanbul Medical School, and 31 consecutive patients aged 8-33 months have been included in the study. Four patients with atrial diameters of over 15 mm and three patients with central nervous system development anomalies were excluded from the study. In order to assess the neuromotor development of patients, neurologic examinations and the Bayley Scales of Infant Development (BSID-III) were used. RESULTS: Nine patients were female (29%) and 22 were male (71%). In the postnatal period, tuberous sclerosis was found in one patient, Down syndrome in one, and equinovarus foot deformity in one. Atrial diameter was <12 mm in 18 patients and >12 mm in 13. Cranial ultrasounds done in the first postnatal month revealed persisting ventriculomegaly in nine patients. The two patients who scored significantly low in all areas on the Bayley Scales of Infant Development were the patients with Down syndrome and tuberous sclerosis. The one scoring low in the motor area was the patient with the equinovarus foot deformity. The BSID-III scores of the patients whose prenatal ventricle diameter was <12 mm were within normal limits. The four patients showing slight developmental delay were the ones whose cranial ultrasound in the first postnatal month showed persisting ventriculomegaly. CONCLUSION: In patients with borderline fetal ventriculomegaly, atrial diameter being more than 12 mm, the condition persisting in the first postnatal month and the presence of accompanying syndromes and malformations all constitute clear risk factors for neurodevelopmental outcome.

In utero phenotyping of mouse embryonic vasculature with MRI.

The vasculature is the earliest developing organ in mammals and its proper formation is critical for embryonic survival. MRI approaches have been used previously to analyze complex three-dimensional vascular patterns and defects in fixed mouse embryos. Extending vascular imaging to an in utero setting with potential for longitudinal studies would enable dynamic analysis of the vasculature in normal and genetically engineered mouse embryos, in vivo. In this study, we employed an in utero MRI approach that corrects for motion, using a combination of interleaved gated acquisition and serial coregistration of rapidly acquired three-dimensional images. We tested the potential of this method by acquiring and analyzing images from wildtype and Gli2 mutant embryos, demonstrating a number of Gli2 phenotypes in the brain and cerebral vasculature. These results show that in utero MRI can be used for in vivo phenotype analysis of a variety of mutant mouse embryos.