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Vascular adaptation to a dysfunctional endothelium as a consequence of Shb deficiency

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Abstract

Vascular endothelial growth factor (VEGF)-A regulates angiogenesis, vascular morphology and permeability by signaling through its receptor VEGFR-2. The Shb adapter protein has previously been found to relay certain VEGFR-2 dependent signals and consequently vascular physiology and structure was assessed in Shb knockout mice. X-ray computed tomography of vessels larger than 24 μm diameter (micro-CT) after contrast injection revealed an increased frequency of 48–96 μm arterioles in the hindlimb calf muscle in Shb knockout mice. Intravital microscopy of the cremaster muscle demonstrated a less regular vasculature with fewer branch points and increased vessel tortuosity, changes that led to an increased blood flow velocity. Reduced in vivo angiogenesis was observed in Shb knockout Matrigel™ plugs. Unlike the wild-type situation, VEGF-A did not provoke a dissociation of VE-cadherin from adherens junctions in Shb knockout venules. The reduced angiogenesis and altered properties of junctions had consequences for two patho-physiological responses to arterial occlusion: vascular permeability was reduced in the Shb knockout cremaster muscle after ligation of one supplying artery and heat-induced blood flow determined by Laser-Doppler measurements was decreased in the hindlimb after ligation of the femoral artery. Consequently, the Shb knockout mouse exhibited structural and functional (angiogenesis and vascular permeability) vascular abnormalities that have implications for understanding the function of VEGF-A under physiological conditions.

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Acknowledgments

We are grateful to Marianne Ljungkvist for help with SEM and Ying Gou for help with blood flow measurements. The work was supported by the Swedish Cancer Foundation (100494), the Swedish Research Council (K2011-54X-10822), the Swedish Diabetes Fund and Family Ernfors Fund.

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The authors declare no conflicts of interests.

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Authors and Affiliations

  1. Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75123, Uppsala, Sweden

    Gustaf Christoffersson, Guangxiang Zang, Evelina Vågesjö, Mia Phillipson & Michael Welsh

  2. Department of Cardiovascular Medicine, Yale University, New Haven, CT, USA

    Zhen W. Zhuang & Michael Simons

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  1. Gustaf Christoffersson
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  2. Guangxiang Zang
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  3. Zhen W. Zhuang
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  4. Evelina Vågesjö
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  7. Michael Welsh
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Correspondence to Michael Welsh.

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Gustaf Christoffersson and Guangxiang Zang have equally contributed.

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Christoffersson, G., Zang, G., Zhuang, Z.W. et al. Vascular adaptation to a dysfunctional endothelium as a consequence of Shb deficiency. Angiogenesis 15, 469–480 (2012). https://doi.org/10.1007/s10456-012-9275-z

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