title: Deficiency in matrix metalloproteinase-2 results in long-term vascular instability and regression in the injured mouse spinal cord.
abstract: Angiogenesis plays a critical role in wound healing after spinal cord injury. Therefore, understanding the events that regulate angiogenesis has considerable relevance from a therapeutic standpoint. We evaluated the contribution of matrix metalloproteinase (MMP)-2 to angiogenesis and vascular stability in spinal cord injured MMP-2 knockout and wildtype (WT) littermates. While MMP-2 deficiency resulted in reduced endothelial cell division within the lesioned epicenter, there were no genotypic differences in vascularity (vascular density, vascular area, and endothelial cell number) over the first two weeks post-injury. However, by 21days post-injury MMP-2 deficiency resulted in a sharp decline in vascularity, indicative of vascular regression. Complementary in vitro studies of brain capillary endothelial cells confirmed MMP-2 dependent proliferation and tube formation. As deficiency in MMP-2 led to prolonged MMP-9 expression in the injured spinal cord, we examined both short-term and long-term exposure to MMP-9 in vitro. While MMP-9 supported endothelial tube formation and proliferation, prolonged exposure resulted in loss of tubes, findings consistent with vascular regression. Vascular instability is frequently associated with pericyte dissociation and precedes vascular regression. Quantification of PDGFrβ+ pericyte coverage of mature vessels within the glial scar (the reactive gliosis zone), a known source of MMP-9, revealed reduced coverage in MMP-2 deficient animals. These findings suggest that acting in the absence of MMP-2, MMP-9 transiently supports angiogenesis during the early phase of wound healing while its prolonged expression leads to vascular instability and regression. These findings should be considered while developing therapeutic interventions that block MMPs.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA. Electronic address: alpa.mahuvakar@ucsf.edu.
authors.forename: Alpa
authors.initials: A
authors.lastname: Trivedi
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Haoqian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Adanma
authors.initials: A
authors.lastname: Ekeledo
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Sangmi
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143, USA.
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305-5454, USA.
authors.forename: Giles W
authors.initials: GW
authors.lastname: Plant
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA; Physical Therapy and Rehabilitation Sciences, University of California, San Francisco, CA 94143, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Noble-Haeusslein
keywords: Angiogenesis; Contusion injury; Matrix metalloproteinases; PDGFrβ positive pericytes; Proliferation; Vascular regression; Vascularity