title: Bioelectric impact of pathological angiogenesis on vascular function.
abstract: Pathological angiogenesis, as seen in many inflammatory, immune, malignant, and ischemic disorders, remains an immense health burden despite new molecular therapies. It is likely that further therapeutic progress requires a better understanding of neovascular pathophysiology. Surprisingly, even though transmembrane voltage is well known to regulate vascular function, no previous bioelectric analysis of pathological angiogenesis has been reported. Using the perforated-patch technique to measure vascular voltages in human retinal neovascular specimens and rodent models of retinal neovascularization, we discovered that pathological neovessels generate extraordinarily high voltage. Electrophysiological experiments demonstrated that voltage from aberrantly located preretinal neovascular complexes is transmitted into the intraretinal vascular network. With extensive neovascularization, this voltage input is substantial and boosts the membrane potential of intraretinal blood vessels to a suprahyperpolarized level. Coincident with this suprahyperpolarization, the vasomotor response to hypoxia is fundamentally altered. Instead of the compensatory dilation observed in the normal retina, arterioles constrict in response to an oxygen deficiency. This anomalous vasoconstriction, which would potentiate hypoxia, raises the possibility that the bioelectric impact of neovascularization on vascular function is a previously unappreciated pathophysiological mechanism to sustain hypoxia-driven angiogenesis.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105 dgpuro@umich.edu.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Puro
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105;
authors.forename: Ryohsuke
authors.initials: R
authors.lastname: Kohmoto
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gardner
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105;
authors.forename: Dolly A
authors.initials: DA
authors.lastname: Padovani-Claudio
mesh_terms: D000818:Animals; D004560:Electricity; D004594:Electrophysiology / Q000295:instrumentation / Q000379:methods; D006801:Humans; D000860:Hypoxia; D008564:Membrane Potentials / Q000502:physiology; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D020318:Rats, Long-Evans; D012160:Retina / Q000503:physiopathology; D015861:Retinal Neovascularization / Q000503:physiopathology*; D012171:Retinal Vessels / Q000503:physiopathology*; D014661:Vasoconstriction / Q000502:physiology
keywords: neovascularization; proliferative diabetic retinopathy; proliferative retinopathy; retina; retinopathy of prematurity