Endothelial cells and macrophages play critical roles in maintaining brain health, both under normal conditions and in disease. These cells interact closely, forming the neurovascular unit, which includes endothelial cells, pericytes, smooth muscle cells, astrocytes, neurons, and myeloid cells like microglia and CNS-associated macrophages (CAMs). Recent studies show that these cells share a common origin from erythromyeloid progenitor cells and have overlapping functions in development and disease. Microglia and CAMs regulate vascular function, blood flow, the blood-brain barrier (BBB), and the removal of vascular calcification. In turn, endothelial cells influence the activation and polarization of myeloid cells. The molecular mechanisms governing their interactions are being uncovered, with implications for diseases such as stroke, multiple sclerosis, and Alzheimer’s disease. Microglia and perivascular macrophages (PvMΦ) are particularly important in regulating BBB permeability and neuroinflammation. They interact with endothelial cells through various mechanisms, including the release of cytokines, chemokines, and extracellular vesicles. These interactions can either protect or damage the BBB, depending on the context. For example, microglia can enhance BBB integrity under physiological conditions but may contribute to BBB disruption during pathological states such as ischemia or neuroinflammation. PvMΦ also play a role in vascular remodeling and ECM regulation, influencing fluid dynamics and waste clearance in the brain. Macrophages, including microglia and PvMΦ, modulate cerebral blood flow (CBF) and hypoperfusion. They can influence vascular tone, angiogenesis, and the survival or death of endothelial cells. In conditions like stroke or neuroinflammation, macrophages can either protect or exacerbate vascular damage, depending on their activation state. For instance, microglia depletion can lead to increased BBB permeability and brain edema, while certain macrophage subsets may promote vascular repair. PvMΦ are also involved in phagocytosis, removing waste products, iron deposits, and myelin debris. They contribute to the clearance of vascular calcifications and may play a role in neurodegenerative diseases like Alzheimer’s and cerebral amyloid angiopathy (CAA). However, their function can be impaired in diseases such as CADASIL, where perivascular spaces are enlarged and associated with inflammatory responses. Overall, the interactions between endothelial cells and macrophages are complex and context-dependent, with significant implications for brain health and disease. Understanding these interactions could lead to new therapeutic strategies for neurological disorders.Endothelial cells and macrophages play critical roles in maintaining brain health, both under normal conditions and in disease. These cells interact closely, forming the neurovascular unit, which includes endothelial cells, pericytes, smooth muscle cells, astrocytes, neurons, and myeloid cells like microglia and CNS-associated macrophages (CAMs). Recent studies show that these cells share a common origin from erythromyeloid progenitor cells and have overlapping functions in development and disease. Microglia and CAMs regulate vascular function, blood flow, the blood-brain barrier (BBB), and the removal of vascular calcification. In turn, endothelial cells influence the activation and polarization of myeloid cells. The molecular mechanisms governing their interactions are being uncovered, with implications for diseases such as stroke, multiple sclerosis, and Alzheimer’s disease. Microglia and perivascular macrophages (PvMΦ) are particularly important in regulating BBB permeability and neuroinflammation. They interact with endothelial cells through various mechanisms, including the release of cytokines, chemokines, and extracellular vesicles. These interactions can either protect or damage the BBB, depending on the context. For example, microglia can enhance BBB integrity under physiological conditions but may contribute to BBB disruption during pathological states such as ischemia or neuroinflammation. PvMΦ also play a role in vascular remodeling and ECM regulation, influencing fluid dynamics and waste clearance in the brain. Macrophages, including microglia and PvMΦ, modulate cerebral blood flow (CBF) and hypoperfusion. They can influence vascular tone, angiogenesis, and the survival or death of endothelial cells. In conditions like stroke or neuroinflammation, macrophages can either protect or exacerbate vascular damage, depending on their activation state. For instance, microglia depletion can lead to increased BBB permeability and brain edema, while certain macrophage subsets may promote vascular repair. PvMΦ are also involved in phagocytosis, removing waste products, iron deposits, and myelin debris. They contribute to the clearance of vascular calcifications and may play a role in neurodegenerative diseases like Alzheimer’s and cerebral amyloid angiopathy (CAA). However, their function can be impaired in diseases such as CADASIL, where perivascular spaces are enlarged and associated with inflammatory responses. Overall, the interactions between endothelial cells and macrophages are complex and context-dependent, with significant implications for brain health and disease. Understanding these interactions could lead to new therapeutic strategies for neurological disorders.