The anatomy and immunology of vasculature in the central nervous system

Abstract

Barriers between circulation and the central nervous system (CNS) play a key role in the development and modulation of CNS immune responses. Structural variations in the vasculature traversing different anatomical regions within the CNS strongly influence where and how CNS immune responses first develop. Here, we provide an overview of cerebrovascular anatomy, focusing on the blood-CNS interface and how anatomical variations influence steady-state immunology in the compartment. We then discuss how CNS vasculature is affected by and influences the development of different pathophysiological states, such as CNS autoimmune disease, cerebrovascular injury, cerebral ischemia, and infection.

Fig. 1.. Structural variations in the anatomy of cerebrovascular barriers.

Coronal depiction of cerebrum and dura mater in relation to the middle cerebral and middle meningeal arteries. (A) Meningeal and cortical vascular anatomy. The dura mater contains lymphatics and fenestrated blood vessels that lack tight junctions. The arachnoid mater is an epithelial layer that provides a barrier between the peripheral vasculature of the dura mater and the CSF through tight junctions and efflux pumps. Leptomeningeal blood vessels in the pia mater lack astrocytic ensheathment, but their endothelial cells are connected by tight junctions. There are small stomata in the connective tissue (fibroblastic reticular cells) covering pial vessels that allow an exchange of fluid between the CSF and perivascular space. Pial arteries penetrate the brain and are covered by a densely packed perivascular layer of astrocytic foot processes; astrocytic (pink), pial (gray), and endothelial (purple) basement membranes; and smooth muscle cells. Veins exiting the parenchyma have a perivascular space flanked by astrocytic foot processes as well as endothelial basement membranes (BMs). The pial BM is only present in the superficial portion of the veins. (B) Capillary and postcapillary venule within the brain parenchyma. The capillary endothelial BM (purple) is juxtaposed to the astrocytic BM (pink), whereas the postcapillary venule is surrounded by a perivascular CSF-filled space that separates the endothelial BM from the astrocytic BM. Fibroblast-like cells (green) form an interrupted extension of the pia mater in the postcapillary venules. (C) Vessels in the choroid plexus are fenestrated and lack tight junctions. The ependymal cells overlying the choroid plexus have tight junctions that are tasked with forming a blood-CSF barrier. (D) Vasculatures at the center of CVOs (such as the subfornical organ) are fenestrated and lack tight junctions, allowing exposure to solutes from the circulation. Vasculatures around the perimeter of CVOs have a traditional BBB surrounded by astrocytic foot processes and more closely resemble vessels found in the CNS parenchyma. Overlying ependymal tanycytes are highly specialized cells with tight junctions that separate CVOs from the CSF.

Fig. 2.. Schematic representation of a cortical cerebrovascular bed.

Leptomeningeal arteries penetrate the cortex, giving rise to arterioles, capillaries, and postcapillary venules that lastly drain into cortical veins that exit the parenchyma. Leptomeningeal arteries and veins are surrounded by fibroblast-like cells and a collagen layer. Penetrating arteries are ensheathed by smooth muscle cells (SMCs) that transition to a pericyte layer at arteriole branch points. The pial layer of fibroblast-like cells ends abruptly at the transition from arteriole to capillary. In capillaries, the astrocytic BM (pink) is adjacent to the endothelial cell BM (purple). These membranes separate at the level of the postcapillary venule to form a perivascular space. Interrupted fibroblast-like cells are also present along postcapillary venules and veins as they exit the CNS parenchyma.

Fig. 3.. Anatomy of parenchymal capillary barriers.

Tight junction proteins—such as occludin; claudin-3, claudin-5, and claudin-12; and ZO-1 and ZO-2—and JAMs form tight junctions between cerebrovascular endothelial cells that limit the passage of materials from the blood into the CNS. These are linked to the actin cytoskeleton within endothelial cells. Vascular endothelial cadherins and intracellular catenins form adherens junctions that provide tensile force between endothelial cells through linkage to the actin cytoskeleton. The endothelial BM is primarily composed of laminins α4 and α5 and is juxtaposed to the astrocytic BM, which is composed of laminins α1 and α2. The endothelial cells interact with the basal lamina through α and β integrins that bind to laminins and fibronectin. Similarly, astrocytic endfeet interact with BM through integrins and dystroglycan.

Fig. 4.. Blood-CNS interface during inflammation.

This schematic of a CNS blood vessel summarizes three different immunological scenarios: steady-state T cell surveillance, CNS autoimmune disease, and cerebrovascular injury and stroke. T cell surveillance: During steady state, leukocyte extravasation across the BBB is limited to few activated T lymphocytes that interact with ICAM-1 and VCAM-1 expressed on the lumen of vascular endothelial cells. CXCL12 expression by endothelial cells on the abluminal side contributes to sequestering these activated CD4⁺ T cells in the perivascular space through binding to CXCR4 on the T cell. EAE: During CNS autoimmune diseases such as EAE, the efficiency of leukocyte diapedesis is increased. CCL19, CCL21, and CXCL12 are up-regulated by cerebrovascular endothelial cells that promote the recruitment and adhesion of encephalitogenic CD4⁺ T cells. Vascular adherence and extravasation are also facilitated by selectins (P-selectin–PSGL-1 interactions) and integrins (LFA-1–ICAM-1 and VLA-4–VCAM-1 interactions). CXCR7, expressed on the abluminal surface of endothelial cells, binds to CXCL12 and reduces T cell sequestration in the perivascular space. After extravasation, T cells interact with APCs, including perivascular macrophages (PVMs), in the perivascular space. Recognition of cognate-peptide MHC complexes results in production of chemokines and cytokines (such as TNFα and granulocyte-macrophage colony-stimulating factor) that promote recruitment of myelomonocytic cells from the blood. This is followed by production of metalloproteinases (such as MMP-2 and MMP-9) that selectively cleave dystroglycan in the astrocytic foot processes, allowing penetration of effector T cells into the CNS parenchyma. Vascular injury and stroke: Mechanical disruption of the glia limitans leads to a rapid release of ATP that is detected by purinergic receptors expressed on microglia. The microglia provide immediate barrier support and debris clearance. Cerebrovascular injury can also cause resident and infiltrating monocyte-derived macrophages to release cytokines (TNFα and IL-1β), chemokines, ROS, and metalloproteinases (pro–MMP-9). TNFα and IL-1β trigger endothelial cell activation, promoting further myelomonocytic cell invasion. Pro–MMP-9 becomes activated by MMP-3, causing additional destruction of the glia limitans. Once in the parenchyma, neutrophils can release ROS and NETs in an attempt to control pathogens that are not present. These effector mechanisms contribute to tissue damage.