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it protects the CNS from infection and inflammation. The circuits. 21,68 One of the key aspects of neurovascular
barrier shields the brain from harmful substances that could interactions is the formation and maintenance of the
otherwise disrupt neuronal function or cause inflammation. BBB, a highly selective barrier that regulates the passage
Maintaining ion homeostasis is another critical role of the of substances between the bloodstream and neural tissue.
BBB. It carefully regulates ion concentrations, particularly The BBB’s integrity relies on the neurovascular unit (NVU),
potassium and sodium, in the brain’s extracellular space which consists of ECs, astrocytes, pericytes, neurons,
to ensure proper neuronal excitability and function. The and extracellular matrix. This unit ensures that the brain
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BBB is also involved in neurovascular coupling, where receives adequate nutrients and oxygen while protecting
astrocytes modulate cerebral blood flow (CBF) and direct it from toxins and pathogens. In addition, neurovascular
blood to active brain regions according to metabolic interactions are essential in neurovascular coupling, a
demands. Moreover, the BBB regulates the transport of process that connects neuronal activity with blood flow.
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essential nutrients, such as glucose and amino acids, into This mechanism ensures that active brain regions receive
the brain while actively removing metabolic waste and sufficient blood supply to meet their metabolic demands.
toxins. This selective permeability is critical for supporting Astrocytes and ECs within the NVU communicate through
the high metabolic demands of neural tissue and preserving signaling pathways to modulate blood vessel diameter,
the brain’s chemical environment, thereby safeguarding allowing for precise control of CBF in response to neuronal
neural health and function. activity. 70,76 Disruptions in neurovascular interactions
can lead to various neurological disorders. For instance,
BBB dysfunction is a key feature of many neurological imbalances in angiogenesis, particularly with the formation
disorders, such as multiple sclerosis, AD, stroke, and of new blood vessels, can contribute to conditions such as
epilepsy. Compromise of the BBB’s integrity can result GBM, where excessive vascular growth supports tumor
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from physical damage, inflammation, and/or disrupted proliferation. Conversely, insufficient angiogenesis may
signaling pathways, leading to increased permeability result in hypoxia and neuronal death. Understanding
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and allowing harmful substances to infiltrate the brain. the mechanisms governing neurovascular interactions is
In neurological diseases such as multiple sclerosis, BBB thus crucial for developing therapeutic strategies to treat
breakdown permits immune cells to invade the brain, vasculature-related neurological conditions. 77
causing inflammation and demyelination. In AD, BBB
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dysfunction is associated with the accumulation of Aβ, 3. Methods for vascularization
which further contributes to neuronal damage. Similarly,
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during a stroke, BBB disruption can lead to edema and ion Ideally, vascularization strategies for BOs should facilitate
the formation of complex, branching vessels with active
imbalances, exacerbating neuronal injury. When the BBB’s blood flow that dynamically respond to changes in oxygen
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permeability increases, larger molecules, such as proteins demand and tissue growth. These strategies should also
and immune cells, can enter the brain parenchyma, resulting preserve the organoid’s cellular structure and establish
in neuroinflammation, oxidative stress, and neuronal
damage. This dysfunction may also promote transcytosis, functional NVUs separated from neuronal tissue by the
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allowing non-specific transport of various molecules BBB. To achieve this, methods for vascularizing BOs can
be classified into four categories: (i) vascular induction
across the ECs, and increase the expression of adhesion techniques that promote multi-lineage differentiation,
molecules, facilitating leukocyte infiltration into the brain (ii) the use of biomimetic materials, such as decellularized
tissue, further exacerbating neurodegeneration. Therefore, extracellular matrix (dECM) to support neurovascular
understanding the mechanisms of BBB dysfunction is vital growth, (iii) engineering approaches such as microfluidics
for developing therapeutic strategies aimed at restoring its and 3D printing to control the cellular microenvironment,
integrity and preventing further neural damage. Advances and (iv) transplantation strategies that integrate organoids
in imaging and molecular techniques have provided into host circulatory systems for nutrient and oxygen
valuable insights into BBB pathophysiology, guiding the supply.
development of targeted treatments and drug delivery
methods for neurological diseases. 75 3.1. Vascular induction techniques
2.4. The importance of neovascularization 3.1.1. Co-culture techniques
Neurovascular interactions are critical for the development, Co-culturing with ECs or their progenitors has become
maintenance, and function of the human brain. Such a widely employed strategy to enhance vascularization in
interactions occur between the brain’s vascular system and BOs (Figure 5A). The integration of ECs into organoids
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neural cells, facilitating a delicate balance that is essential has shown promise in creating human-specific vascular
for various physiological processes, including neurogenesis, architectures in the liver, intestine, kidney, and lung
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metabolic regulation, and the formation of complex neural organoids. Pham et al. differentiated ECs from hiPSCs
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Volume 1 Issue 2 (2025) 7 doi: 10.36922/or.8162