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Four-Dimensional Microvascular Analysis Reveals That Regenerative Angiogenesis in Ischemic Muscle Produces a Flawed Microcirculation.
Arpino, John-Michael; Nong, Zengxuan; Li, Fuyan; Yin, Hao; Ghonaim, Nour; Milkovich, Stephanie; Balint, Brittany; O'Neil, Caroline; Fraser, Graham M; Goldman, Daniel; Ellis, Christopher G; Pickering, J Geoffrey.
Afiliação
  • Arpino JM; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Nong Z; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Li F; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Yin H; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Ghonaim N; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Milkovich S; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Balint B; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • O'Neil C; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Fraser GM; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Goldman D; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Ellis CG; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
  • Pickering JG; From the Robarts Research Institute (J.-M.A., Z.N., F.L., H.Y., B.B., C.O., J.G.P.), Departments of Medicine (C.G.E., J.G.P.), Medical Biophysics (J.-M.A., S.M., B.B., G.M.F., D.G., C.G.E., J.G.P.), Biochemistry (J.G.P.), and Biomedical Engineering (N.G., D.G.), Western University, London, Canada; a
Circ Res ; 120(9): 1453-1465, 2017 Apr 28.
Article em En | MEDLINE | ID: mdl-28174322
ABSTRACT
RATIONALE Angiogenesis occurs after ischemic injury to skeletal muscle, and enhancing this response has been a therapeutic goal. However, to appropriately deliver oxygen, a precisely organized and exquisitely responsive microcirculation must form. Whether these network attributes exist in a regenerated microcirculation is unknown, and methodologies for answering this have been lacking.

OBJECTIVE:

To develop 4-dimensional methodologies for elucidating microarchitecture and function of the reconstructed microcirculation in skeletal muscle. METHODS AND

RESULTS:

We established a model of complete microcirculatory regeneration after ischemia-induced obliteration in the mouse extensor digitorum longus muscle. Dynamic imaging of red blood cells revealed the regeneration of an extensive network of flowing neo-microvessels, which after 14 days structurally resembled that of uninjured muscle. However, the skeletal muscle remained hypoxic. Red blood cell transit analysis revealed slow and stalled flow in the regenerated capillaries and extensive arteriolar-venular shunting. Furthermore, spatial heterogeneity in capillary red cell transit was highly constrained, and red blood cell oxygen saturation was low and inappropriately variable. These abnormalities persisted to 120 days after injury. To determine whether the regenerated microcirculation could regulate flow, the muscle was subjected to local hypoxia using an oxygen-permeable membrane. Hypoxia promptly increased red cell velocity and flux in control capillaries, but in neocapillaries, the response was blunted. Three-dimensional confocal imaging revealed that neoarterioles were aberrantly covered by smooth muscle cells, with increased interprocess spacing and haphazard actin microfilament bundles.

CONCLUSIONS:

Despite robust neovascularization, the microcirculation formed by regenerative angiogenesis in skeletal muscle is profoundly flawed in both structure and function, with no evidence for normalizing over time. This network-level dysfunction must be recognized and overcome to advance regenerative approaches for ischemic disease.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Músculo Esquelético / Microscopia de Vídeo / Microscopia Confocal / Neovascularização Fisiológica / Microvasos / Isquemia / Hipóxia / Microcirculação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Músculo Esquelético / Microscopia de Vídeo / Microscopia Confocal / Neovascularização Fisiológica / Microvasos / Isquemia / Hipóxia / Microcirculação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article