CGRP/CGRP Receptor Antibodies: Potential Adverse Effects Due to Blockade of Neovascularization?

Vasodilating calcitonin gene-related peptide (CGRP), a key neuropeptide in migraine pathophysiology, exhibits proangiogenic and prolymphangiogenic activities. It also sends a cue for neovascularization to modulate recovery from ischemia, healing ulcers and wounds, and lymph edema, and to enhance tumor-associated angiogenesis and tumor growth. In 2018, the FDA approved CGRP/CGRP receptor antibodies that prevent migraine, representing progress over simple relief therapeutics. Long-term administration of CGRP/CGRP receptor antibodies could possibly induce adverse effects related to suppression of neovascularization. CGRP/CGRP receptor antibodies could also suppress tumor-associated angiogenesis. Therapeutic benefits versus neovascularization-related adverse effects from CGRP antibodies should be carefully evaluated over a long-term clinical trial. Migraine is a severe neurological disorder in which calcitonin gene-related peptide (CGRP) is a key molecule in pathophysiology. Neuronal system-derived CGRP enhances neovascularization in several important pathological conditions and sends a cue to the vascular system. In 2018, the FDA approved erenumab and fremanezumab, antibodies against CGRP receptor and CGRP, as the first new class of drugs for migraine. Treatment of migraine with these antibodies requires great care because neovascularization-related adverse effects may be induced in some patients. Here, we focus on enhancement of neovascularization by CGRP and discuss possible adverse effects resulting from blocking neovascularization. We also suggest that CGRP antibodies may also be used as novel antitumor agents by suppressing tumor-associated angiogenesis. Migraine is a severe neurological disorder in which calcitonin gene-related peptide (CGRP) is a key molecule in pathophysiology. Neuronal system-derived CGRP enhances neovascularization in several important pathological conditions and sends a cue to the vascular system. In 2018, the FDA approved erenumab and fremanezumab, antibodies against CGRP receptor and CGRP, as the first new class of drugs for migraine. Treatment of migraine with these antibodies requires great care because neovascularization-related adverse effects may be induced in some patients. Here, we focus on enhancement of neovascularization by CGRP and discuss possible adverse effects resulting from blocking neovascularization. We also suggest that CGRP antibodies may also be used as novel antitumor agents by suppressing tumor-associated angiogenesis. a key regulatory enzyme (EC 4.6.1.1) in all living cells that converts ATP to 3′,5′-cyclic AMP (cAMP) and pyrophosphate. physiological process forming new blood vessels from pre-existing vessels. growth of functional collateral arteries from pre-existing arterio-arteriolar anastomoses. an occlusive arterial disease mainly affecting the abdominal aorta and small/medium-sized arteries of lower extremities. molecules regulating neurons sending out axons to reach their targets. response stimulated by peripheral nerves that travels away from the nerve cell body and branches to stimulate target organs. a potent endothelium-dependent vasodilator, and constrictor of nonvascular smooth muscle in the bronchus and gut, that increases vascular permeability and induces pain sensations. a calcitonin family peptide produced in peripheral and central neurons, and a potent peptide vasodilator functioning in nociception. a G-protein-coupled receptor related to the calcitonin receptor, linked to one of three single transmembrane domain receptor activity-modifying proteins (RAMPs) that are essential for functional activity. formation of new lymphatic vessels from pre-existing lymphatic vessels, important in homeostasis, metabolism, and immunity. Abnormal lymphangiogenesis contributes to pathological conditions, including neoplasm metastasis, edema, rheumatoid arthritis, psoriasis, and impaired wound healing. accumulation of lymph fluid in soft tissues, especially arms and legs. Protein-rich lymph fluid is normally filtered by lymph nodes, then released into the bloodstream. When nodes are obstructed or removed, lymph flow is hampered, causing swelling. a class of macrophages connected with Th2 immune response. They also contribute to production of extracellular matrix components, tissue remodeling, and neovascularization. a gas signaling molecule involved in many physiological and pathological processes, including vasodilatation. NO is produced from L-arginine by NO synthase. a class of drugs that reduce pain, decrease fever, prevent blood clots, and inhibit inflammation by inhibiting cyclooxygenase enzymes COX-1 and COX-2. a highly conserved cell signaling system present in most multicellular organisms that promotes proliferation during neurogenesis and regulates embryonic development. a part of the spinal nucleus of the trigeminal nerve. At the central synapses in the trigeminal nucleus caudalis, CGRP acts on second-order neurons to transmit pain signals to the thalamus and higher cortical pain regions. a form of cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells. physiologically active lipids with diverse biological activities derived enzymatically from fatty acids. Prostaglandins induce vasodilation, inhibit platelet aggregation, enhance inflammation by influencing vasodilation, and sensitize peripheral nerves to amplify pain. a component of the CGRP receptor. RAMPs interact with and modulate several class B G-protein-coupled receptors, including receptors for secretin, calcitonin, glucagon, vasoactive intestinal peptide, and adrenomedullin. There are three distinct types of RAMPs in mammals (RAMP1–3), encoded by separate genes. RCP, CLR, and RAMP1 constitute a functional CGRP receptor. RCP is an intracellular protein required for G-protein-coupled signal transduction at receptors for the neuropeptide CGRP. principal glia cells of the peripheral nervous system that form a myelin sheath around axons of motor and sensory neurons. sensory ganglion of the trigeminal nerve that occupies a cavity (Meckel's cave) in the dura mater. This fifth cranial nerve is responsible for facial sensation and motor functions, including biting and chewing. Sensory functions provide tactile, proprioceptive, and nociceptive afference to the face and mouth. a family of tryptamine-based drugs used in the treatment of migraines and cluster headaches. a signal protein that stimulates the formation of blood vessels and lymphatics. In mammals, there are five members: VEGF-A, placenta growth factor (PlGF), VEGF-B, VEGF-C, and VEGF-D. All members stimulate cellular responses by binding to tyrosine kinase receptors. a process of blood vessel formation occurring by a de novo production of endothelial cells, in which endothelial precursor cells migrate and differentiate in response to local cues to form new blood vessels.