Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy

Kengo F. Kusano, Karen L. Allendoerfer, William Munger, Roberto Pola, Marta Bosch-Marce, Rudolf Kirchmair, Youngsup Yoon, Cynthia Curry, Marcy Silver, Marianne Kearney, Takayuki Asahara, Douglas W. Losordo

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Abstract

Objective - The embryonic morphogen sonic hedgehog (SHh) has been shown to induce neovascularization of ischemic tissue but has not been shown to play a role in regulating vascular nerve supply. Accordingly, we investigated the hypothesis that systemic injection of SHh protein could improve nerve blood flow and function in diabetic neuropathy (DN). Methods and Results - Twelve weeks after induction of diabetes with streptozotocin, motor and sensory nerve conduction velocities (MCV and SCV) of the sciatic nerves were significantly reduced in diabetic rats. SHh-treated diabetic rats demonstrated marked improvement of both MCV and SCV (P<0.05). Laser Doppler perfusion imaging showed that nerve blood flow was significantly reduced in the diabetic rats but was restored in SHh-treated diabetic rats (P<0.05 versus diabetic saline-treated rats) to levels similar to those achieved with vascular endothelial growth factor-2 (VEGF-2) gene therapy. In vivo perfusion of Bandeuraea simplicifolia (BS)-1 lectin showed marked reduction in the vasa nervora in diabetic sciatic nerves but restoration of nerve vasculature to nondiabetic levels in the SHh-treated and plasmid DNA encoding human VEGF-2 (phVEGF-2)-treated diabetic nerves. Interestingly, the SHh-induced vasculature was characterized by larger diameter and more smooth muscle cell-containing vessels, compared with VEGF-2 gene-treated diabetic rats. Conclusions - These data indicate that Shh induces arteriogenesis and restores nerve function in DN.

Original languageEnglish
Pages (from-to)2102-2107
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume24
Issue number11
DOIs
Publication statusPublished - 2004 Nov 1

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Vasa Nervorum
Hedgehogs
Diabetic Neuropathies
Sciatic Nerve
Vascular Endothelial Growth Factor A
Hedgehog Proteins
Perfusion Imaging
Experimental Diabetes Mellitus
Neural Conduction
Lectins
Genetic Therapy
Smooth Muscle Myocytes
Blood Vessels
Lasers
Plasmids
Perfusion
Injections
DNA

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Kusano, K. F., Allendoerfer, K. L., Munger, W., Pola, R., Bosch-Marce, M., Kirchmair, R., ... Losordo, D. W. (2004). Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(11), 2102-2107. https://doi.org/10.1161/01.ATV.0000144813.44650.75
Kusano, Kengo F. ; Allendoerfer, Karen L. ; Munger, William ; Pola, Roberto ; Bosch-Marce, Marta ; Kirchmair, Rudolf ; Yoon, Youngsup ; Curry, Cynthia ; Silver, Marcy ; Kearney, Marianne ; Asahara, Takayuki ; Losordo, Douglas W. / Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2004 ; Vol. 24, No. 11. pp. 2102-2107.
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Kusano, KF, Allendoerfer, KL, Munger, W, Pola, R, Bosch-Marce, M, Kirchmair, R, Yoon, Y, Curry, C, Silver, M, Kearney, M, Asahara, T & Losordo, DW 2004, 'Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 11, pp. 2102-2107. https://doi.org/10.1161/01.ATV.0000144813.44650.75

Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy. / Kusano, Kengo F.; Allendoerfer, Karen L.; Munger, William; Pola, Roberto; Bosch-Marce, Marta; Kirchmair, Rudolf; Yoon, Youngsup; Curry, Cynthia; Silver, Marcy; Kearney, Marianne; Asahara, Takayuki; Losordo, Douglas W.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 24, No. 11, 01.11.2004, p. 2102-2107.

Research output: Contribution to journalArticle

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T1 - Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy

AU - Kusano, Kengo F.

AU - Allendoerfer, Karen L.

AU - Munger, William

AU - Pola, Roberto

AU - Bosch-Marce, Marta

AU - Kirchmair, Rudolf

AU - Yoon, Youngsup

AU - Curry, Cynthia

AU - Silver, Marcy

AU - Kearney, Marianne

AU - Asahara, Takayuki

AU - Losordo, Douglas W.

PY - 2004/11/1

Y1 - 2004/11/1

N2 - Objective - The embryonic morphogen sonic hedgehog (SHh) has been shown to induce neovascularization of ischemic tissue but has not been shown to play a role in regulating vascular nerve supply. Accordingly, we investigated the hypothesis that systemic injection of SHh protein could improve nerve blood flow and function in diabetic neuropathy (DN). Methods and Results - Twelve weeks after induction of diabetes with streptozotocin, motor and sensory nerve conduction velocities (MCV and SCV) of the sciatic nerves were significantly reduced in diabetic rats. SHh-treated diabetic rats demonstrated marked improvement of both MCV and SCV (P<0.05). Laser Doppler perfusion imaging showed that nerve blood flow was significantly reduced in the diabetic rats but was restored in SHh-treated diabetic rats (P<0.05 versus diabetic saline-treated rats) to levels similar to those achieved with vascular endothelial growth factor-2 (VEGF-2) gene therapy. In vivo perfusion of Bandeuraea simplicifolia (BS)-1 lectin showed marked reduction in the vasa nervora in diabetic sciatic nerves but restoration of nerve vasculature to nondiabetic levels in the SHh-treated and plasmid DNA encoding human VEGF-2 (phVEGF-2)-treated diabetic nerves. Interestingly, the SHh-induced vasculature was characterized by larger diameter and more smooth muscle cell-containing vessels, compared with VEGF-2 gene-treated diabetic rats. Conclusions - These data indicate that Shh induces arteriogenesis and restores nerve function in DN.

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