During development, guidance molecules regulate both cell migration and blood vessel growth in many organs, including the central nervous system (CNS). These guidance molecules can act as pro- or antiangiogenic cues. Growing evidence indicates that in the adult brain, guidance molecules play important roles in neurovascular stability. Following ischemic injury, many guidance molecules are upregulated in ischemic areas in the CNS and other organs. Interference with guidance molecules following ischemic injury can affect vascular repair and regeneration and thus influence functional outcomes in preclinical models including cerebral stroke. So far, experimental proangiogenic approaches in the CNS have mostly focused on VEGF supplementation, with limited success partly due to detrimental effects of the treatment, including increased blood–brain barrier (BBB) leakage. Some guidance molecules have proangiogenic properties without apparent negative effects on the BBB. Guidance molecules and their receptors, given their potential dual positive effects on both nerve fiber and vascular regeneration, may represent advantageous targets for the development of new therapies to 'refuel' and repair the damaged CNS. Stroke patients have only limited therapeutic options and often remain with considerable disabilities. To promote neurological recovery, angiogenesis in the ischemic peri-infarct region has been recognized as an encouraging therapeutic target. Despite advances in mechanistic understanding of vascular growth and repair, effective and safe angiogenic treatments are currently missing. Besides the most intensively studied angiogenic growth factors, recent research has indicated that the process of vascular sprouting and migration also requires the participation of guidance molecules, many of which were initially identified as regulators of axonal growth. Here, we review the inhibitory and growth-promoting effects of guidance molecules on the vascular system and discuss their potential as novel angiogenic targets for neurovascular diseases. Stroke patients have only limited therapeutic options and often remain with considerable disabilities. To promote neurological recovery, angiogenesis in the ischemic peri-infarct region has been recognized as an encouraging therapeutic target. Despite advances in mechanistic understanding of vascular growth and repair, effective and safe angiogenic treatments are currently missing. Besides the most intensively studied angiogenic growth factors, recent research has indicated that the process of vascular sprouting and migration also requires the participation of guidance molecules, many of which were initially identified as regulators of axonal growth. Here, we review the inhibitory and growth-promoting effects of guidance molecules on the vascular system and discuss their potential as novel angiogenic targets for neurovascular diseases. formation of new blood vessels from preexisting vasculature, mostly by sprouting. the highly motile tip of a developing or regenerating axon that senses attractive and repulsive cues and gradients in the environment. highly selective border formed mainly by vascular ECs and their tight junctions, which separates circulating blood from the brain parenchyma and extracellular fluid in the CNS. in clinical practice, acute restoration of blood flow after stroke is mainly achieved either through enzymatic thrombolysis by the application of recombinant tissue plasminogen activator or through endoscopic thrombectomy. In general, both procedures have to be applied within a 4–6-h time window after the stroke. Under certain conditions, mechanical thrombectomy is reasonable within 16–24 h for patients with large vessel occlusions in the anterior circulation. a leading cell at the tip of a developing or regenerating vascular sprout that senses attractive and repulsive cues in the environment. projections of the cell edge filled with actin cytoskeleton that are largely responsible for the motile dynamics of axonal growth cones and endothelial tip cells. occurs when blood clot occludes a cerebral vessel; high risk of cell death in the affected area. signals from the extracellular environment or neighboring cells to attract or repel cells according to their receptor repertoire. They play major roles in early embryonic pattern and organ formation, nerve fiber and vascular growth, and cancer cell migration. complication of ischemic stroke by leakage of blood into the brain parenchyma; can occur after thrombolytic therapy or from immature, growing vessels in the stroke penumbra. space between compartmental divisions of an embryo's body during early development. local route of administration through a cerebral ventricle directly into the cerebrospinal fluid; mostly used for substances that may not pass the BBB. the majority of ischemic strokes in patients result from blockage of blood vessels in the territory of the MCA. A common experimental stroke model to mimic this scenario in rodents is proximal or distal occlusion of the MCA, most commonly through the permanent or transient insertion of a filament into the internal carotid artery. a complex functional and anatomical structure comprising ECs, neurons, pericytes, astrocytes, and microglia. ischemia-induced neovascularization is a common feature of retinal vascular diseases such as diabetic retinopathy or retinopathy of prematurity. To investigate the pathological mechanisms, a mouse model is has been developed that is based on the transient exposure of mouse pups to hyperoxia during retinal vascular development. Return to normoxia results in retinal ischemia followed by proliferative vascular disease. common diabetic complication in the eye; damage to retinal arteries ultimately results in pathological neoangiogenesis, which damages the retina and may cause blindness. occlusion of the retinal vasculature, which may lead to the rapid death of retinal neurons. family of G-proteins; known to regulate many aspects of the actin cytoskeleton and cell motility. life-threatening immune response to infection, which causes injury to the body's own tissues and organs. abnormal mass of tumor tissue that usually does not contain cysts or liquid areas. They might be benign or malignant. capacity of a blood vessel wall to allow the passage of small molecules, large substances, or cells; can be altered through drugs or pathologies. vascular endothelial growth factor and its most important receptor; The most prominent and conserved signaling pathway to induce angiogenic responses in development and disease.

Refueling the Ischemic CNS: Guidance Molecules for Vascular Repair