title: Nerve growth factor stimulates regeneration of perivascular nerve, and induces the maturation of microvessels around the injured artery.
abstract: An immature vasa vasorum in the adventitia of arteries has been implicated in induction of the formation of unstable atherosclerotic plaques. Normalization/maturation of the vasa vasorum may be an attractive therapeutic approach for arteriosclerotic diseases. Nerve growth factor (NGF) is a pleotropic molecule with angiogenic activity in addition to neural growth effects. However, whether NGF affects the formation of microvessels in addition to innervation during pathological angiogenesis is unclear. In the present study, we show a new role for NGF in neovessels around injured arterial walls using a novel in vivo angiogenesis assay. The vasa vasorum around arterial walls was induced to grow using wire-mediated mouse femoral arterial injury. When collagen-coated tube (CCT) was placed beside the injured artery for 7-14 days, microvessels grew two-dimensionally in a thin layer on the CCT (CCT-membrane) in accordance with the development of the vasa vasorum. The perivascular nerve was found at not only arterioles but also capillaries in the CCT-membrane. Biodegradable hydrogels containing VEGF and NGF were applied around the injured artery/CCT. VEGF significantly increased the total length and instability of microvessels within the CCT-membrane. In contrast, NGF induced regeneration of the peripheral nerve around the microvessels and induced the maturation and stabilization of microvessels. In an ex vivo nerve-free angiogenesis assay, although NGF potentially stimulated vascular sprouting from aorta tissues, no effects of NGF on vascular maturation were observed. These data demonstrated that NGF had potent angiogenic effects on the microvessels around the injured artery, and especially induced the maturation/stabilization of microvessels in accordance with the regeneration of perivascular nerves.
authors.affiliation: Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asanome
authors.affiliation: Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan. Electronic address: kawabeju@asahikawa-med.ac.jp.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kawabe
authors.affiliation: Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Matsuki
authors.affiliation: Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kabara
authors.affiliation: Department of Anatomy, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hira
authors.affiliation: Department of Anatomy, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Bochimoto
authors.affiliation: Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Aonuma
authors.affiliation: Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takehara
authors.affiliation: Department of Anatomy, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, Japan; Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hasebe
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D005263:Femoral Artery / Q000187:drug effects* / Q000293:injuries* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects*; D014651:Vasa Vasorum / Q000294:innervation / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D043925:Angiogenesis Inducing Agents; D042461:Vascular Endothelial Growth Factor A; D020932:Nerve Growth Factor
keywords: Angiogenesis; Atherosclerosis; CCT; Innervation; NGF; Neural growth factors; VEGF; Vasa vasorum; collagen-coated tubes; nerve growth factor; vascular endothelial growth factors