Cellular components of central nervous system microvasculature and microenvironment integrity are essential for a correct neurovascular function. (A) Schematic representation of the neurovascular unit. (B) Blood-brain barrier exchange function. Gluc, glucose; Aa, aminoacids; Xb, xenobiotics; AE, astrocyte endfoot; TJ, tight junction; EC, endothelial cell; BM, basement membrane.

Angiogenesis is governed by a dynamic balance of stimulators and inhibitors. In normal brain, angiogenesis is tightly downregulated but ischemic or hypoxic situations in central nervous system lead to an alteration of the physiologic anti- versus pro-angiogenic balance to try to compensate for vessel damage or degeneration. The most potent pro-angiogenic factor is vascular endothelial growth factor, followed by fibroblast growth factor. Pro-angiogenic factors also include transforming growth factor-β1, placental growth factor and interleukins, while notable among anti-angiogenic factors are angiostatin, endostatin and thrombospondins-1 and -2 (Harrigan, 2003; Lawler and Lawler, 2012). Identifying the signals that regulate central nervous system vascularization in health and disease offers new insights for therapeutic strategies against central nervous system diseases.

Overview of the main factors and signaling pathways involved in brain angiogenesis. Schematic representation of the main growth factors and their respective receptors, that trigger the cascade of intracellular signals that induce cell proliferation, survival, permeability, and migration. Especially in hypoxic situations, these pathways, as well as hypoxia-inducible factors (such as HIF-1α and some microRNAs), are stimulated and promote angiogenesis. As shown, some of these factors can interact with each other, leading to synergistic angiogenic effects.

Brain microvasculature damage/decrease is involved in many central nervous diseases. (A) Main central nervous diseases in which a reduction in brain microvasculature has been described. (B) Cascade of events that occur in the illustrated diseases due to the damage/degeneration of the neurovascular unit. BBB, blood-brain-barrier; EC, endothelial cell.

Therapeutic opportunities employed for achieving brain angiogenesis and neurovascular network recovery. The design of the therapeutic strategy can embrace from the simplest form—with no vector—to the most complex approaches combining various technologic systems. During its implementation, relevant issues that should be considered include dosage of the therapeutic agent, concentration and number of doses, time point of administration, duration of the treatment, and the route of administration.