One of the most often used psychotropic substances, ethanol, permeates the placental barrier, and hence exerts potential teratogenic effects. A 2011 survey found that 45 percent of pregnancies in the United States were unintentional, with one in ten pregnant women between the ages of 18 and 44 reporting intake of alcohol in the previous 30 days and one in thirty-three reporting binge drinking [1, 2]. The pattern and intensity of the detrimental effects of prenatal alcohol exposure are dependent on alcohol dose, timing, sequence, and persistence of alcohol intake. All current research indicates that alcohol has a detrimental effect on fetal development. However, the fetal brain is the most substantially afflicted organ, displaying structural and functional abnormalities as a result of maternal alcohol consumption [3, 4]. Exposure to alcohol may result in fetal alcohol spectrum disorders (FASDs) in humans. FASD is a collective name for the harmful effects of prenatal alcohol exposure (PAE), including impairments in physiologic, neurologic, and behavioral development [5]. It should also be noted that FASD is an umbrella term that incorporates a variety of alcohol-related disorders with a range of severity. The most severe type of FASD, fetal alcohol syndrome (FAS) is characterized by specific physical traits in neonates. Partial FAS (pFAS), on the other hand, is diagnosed when there is validated prenatal alcohol exposure but not enough signs and symptoms to confirm a diagnosis of FAS [6]. Recent investigations, however, have seen the effects of alcohol on fetal cerebrovascular function emerge as a key mediator since brain energy needs are usually fulfilled by a continually adjusting blood supply [7]. Such an adaptation begins at the level of cerebral arteries and extends to microvessels that enter the brain parenchyma and form the neurovascular unit [8,9]. PAE may have acute and chronic teratogenic and toxic impacts on cerebrovascular physiology. This review’s objective is to outline the pathological pathways in different developmental phases, as well as their morphological and functional consequences on the cerebral circulation. It is held that alterations of cerebral blood flow (CBF) owing to dysregulation of cerebral blood vessels in PAE may be a significant contributor to the etiology of several cerebrovascular events, such as stroke.

During the early-gestation period, the neural tube is surrounded by a perineural vascular plexus (PNPV) developed by vasculogenesis, the process of blood vessel development in the embryo, which involves the de novo generation of endothelial cells (ECs). Beginning in the mid-gestation period, endothelial cells from the PNPV penetrate the neural parenchyma, utilizing fibers from multipotent stem cells, like radial glia cells from the developing forebrain, to direct their migration toward the ventricular surface, thereby initiating the first vessels of the CNS. The second trimester is crucial for neuronal and blood vessel growth in the fetal brain [10, 11]. During this phase, a network of arteries inside the sub-arachnoid space gives birth to microvessels that enter the fetal brain [11]. This emerging vasculature supports nutritional requirements and endocrine regulation of fetal brain development [12]. In the early-mid gestation period, vascular development in the CNS is mediated by angiogenesis, which is defined as a series of cellular and molecular processes including the production of new vessels and culminates in the formation of the blood-brain barrier (BBB) [13,14,15]. At the mid-late gestation period, interactions among neural cells and ECs are initiated and continue through late-gestation and until birth. Communication between glial cells and the vasculature is crucial for the optimal development of the nervous system [16]. Pericytes increase vascular stability by releasing a variety of stabilization factors, such as angiopoietin-1 (ANG1) and platelet-derived growth factor (PDGF-β), tissue inhibitor of metalloproteinase 3 (TIMP3) [17]. In response to neural impulses at the perivascular terminal, astrocytes produce chemicals capable of regulating vascular tone. From the late-gestation period until birth, the BBB continues to mature via the expression of various molecules by the BBB’s cellular components, culminating in the development of a basal membrane rich in laminin, collagen IV, and fibronectin that fully surrounds the brain vasculature [18].

It has been established that maternal ethanol exposure causes rapid and persistent loss of blood flow from the umbilical artery to the fetal brain, potentially distressing nutrition and the maternal/fetal endocrine environment during a critical stage for neurogenesis and angiogenesis in the developing brain [19]. Because alcohol exposure during pregnancy is known to alter brain development, the majority of investigations have centered on neural cells. At the molecular and subcellular levels, however, cerebrovascular development is a more complicated, multi-step process involving a large number of molecular participants.

Angiogenesis is a complex process that is delicately controlled by a balance between pro-and anti-angiogenic factors [20]. They consist of, but are not limited to, vascular endothelial growth factor (VEGF), integrins, fibronectin, angiopoietins, vascular cell adhesion molecules (VCAM), fibroblast growth factors (FGF), tyrosine kinases (TK), extracellular matrix (ECM) proteins and proteinases, transforming growth factor (TGF), and Wnt signaling factors as growth-stimulatory signals. On the other hand, tumor necrosis factor (TNF) signaling and pro-apoptosis factors are stop signals [21, 22, 23]. Recent research conducted on adult nonhuman primates [24] and mice [25, 26] conclusively demonstrates that alcohol has a deleterious effect on vasculogenesis and angiogenesis pathways. According to microarray investigations, genes (e.g., VEGF gene family) implicated in angiogenesis are molecular targets of ethanol toxicity [27].

In addition to disrupting the signaling components that regulate vascularization and brain development, PAE may affect molecular targets that are particular to cerebrovascular development. Ethanol may affect the molecular and cellular elements of the BBB directly as soon as they are present during CNS development. Other research indicated that the embryonic brain is more susceptible to ethanol due to the high prevalence of proapoptotic proteins and low expression of proteins associated with stress response systems, namely autophagy or unfolded protein response [28]. Also, a proteomics investigation revealed that alcohol-exposed baboon fetuses mainly had changes in mitochondrial and structural proteins in their cerebral arteries. Unlike mitochondrial proteins, structural proteins were downregulated in the brain of fetal arteries exposed to alcohol [29].

Considering ethical limits of human-based research, the PAE of laboratory animals has been extensively used as an alternative. Results from these animal models showed a significant influence on the generation and expression of microvessels in the rodent model. Besides dose, the timing of ethanol exposure has a significant impact on the outcome of fetal brain development. Since the gestational period of rodents (i.e., 18–23 days) is much shorter than that of humans, the morphological and functional effects of alcohol on these animals may need to be extrapolated to equivalent pregnancy terms in humans. In both rats and mice, gestational day (GD) 1–10, GD 10–20, and postnatal days (P) 1–10 can be considered as the equivalents of first, second, and third trimester human pregnancy, respectively [30]. Prior research on rat models exposed to moderate prenatal alcohol dosages revealed ultrastructural changes in brain capillaries at P20–30 [31]. In a study using rat models, the oral administration of 6.6 g/kg of ethanol from P4 to P10 was evaluated at P10 for any alterations in brain microvasculature [32]. There was no change in capillary density, while capillary diameters were increased in the cerebellum and hippocampus regions, unlike the dentate gyrus region [32]. Later, in a mouse model (at P2) of the third trimester equivalent of human pregnancy demonstrated the loss of radial orientation of the microvessels and a reduction in cerebral vascular density when maternal injection of 3 g/kg ethanol occurred during GD 13–19, which was a time-line equal to the second trimester of human pregnancy [33]. Overall, these rodent studies suggest that alcohol exposure during the human mid and late trimesters might affect the microvasculature differentially in the brain regions.

Human embryos are susceptible to ethanol. Evidence suggests that exposure to high amounts of ethanol during human development causes craniofacial, cardiovascular, and neurological abnormalities, which are often accompanied by cognitive and behavioral deficiencies. Autopsy and magnetic resonance imaging (MRI) investigations found that individuals who were exposed to alcohol in utero had structural brain damage, including lower brain sizes and reduced amounts of white and gray matter inside the brain [reviewed in 4]. However, the animal research mentioned earlier suggests that exposure to PAE during late gestation might be perilous. In a postmortem examination of human brain tissues from fetuses that deceased spontaneously in utero, stage-dependent alterations in the cortical vascular network were detected in the cortex of fetuses with FAS. The radial arrangement of cortical microvessels was markedly disrupted in FAS patients after 30 weeks of gestation, whereas no changes were seen in alcohol-exposed human embryonic brain tissues between 20 and 22 weeks of gestation. In addition, dynamic microscopy techniques indicated that alcohol altered endothelial cell activity and survival as well as the plasticity of the microvessel [33].

In conclusion, investigations conducted on rodents and humans suggest that prenatal alcohol consumption, especially during the late stages of gestation, may affect the macroscopical or microscopical structure of the cerebral microvascular network. These age-dependent abnormalities can be theorized because of a disturbance in cortical angiogenesis.

Critical to brain function is a coherence among the metabolic needs, the supply of oxygen and nutrients, and the elimination of cellular waste. This matching requires continual modulation of CBF, which may be divided into four basic categories: autoregulation, vascular reactivity, neurovascular coupling (NVC), and endothelium-dependent responses. Due to the limited scope of this paper, this part of the review will discuss how PAE affects the functional parts of cerebrovascular circulation, with focuses on how it changes CBF and vascular reactivity and the clinical effects of these changes.

Because alcohol is a simple ligand that may concurrently target several chemical entities, its effects on the developing brain are very complicated. Alcohol may cause cell death in some types of brain cells while interfering with the cellular and molecular activities of other types. These effects may be caused by alcohol both directly and indirectly.

Alcohol may have direct effects on embryonic brain development by interfering with neuronal proliferation and migration [62] or by inducing cell death [63,64,65]. In addition, alcohol may raise fetal glutamate levels [66, 67] and decrease glutamate N-methyl-D-aspartate receptors [68, 69], which may result in aberrant neuronal and glial migration.

Alcohol-induced hypoxia in the fetus is a significant indirect cause of alcohol. Alcohol reduces blood flow to the umbilical artery [70, 71], which might result in growth retardation [72, 73]. In addition to inhibiting protein synthesis and altering hormone levels, alcohol may further impede development [74, 75]. Increased oxidative stress on the embryo [76, 77] and disruption of growth factor signaling [78, 79] are additional pathways.

These effects can be toxic (short-term) and teratogenic (long-term). This section will examine as well as summarize (Table 1) the toxic and teratogenic processes that generate short-term or long-term effects on the cerebral arteries and microvessel network.

There is currently no readily available treatment for intentional or unintentional alcohol intake during pregnancy. The inadequate mechanistic knowledge of FASD’s pathogenesis is one of the explanations. More research is required to understand the underlying mechanisms through which alcohol might affect the structure and function of cells. Understanding these multiple mechanisms and seeking to inhibit them may help us to reduce the negative effects of alcohol exposure on embryonic development in the future. Additionally, efforts must be made to improve public awareness of the detrimental consequences of even little alcohol intake during pregnancy.