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Endothelial β1-integrins are necessary for microvascular function and glucose uptake.

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Title: Endothelial β1-integrins are necessary for microvascular function and glucose uptake.
Authors: Winn, Nathan C., Roby, Deborah A., McClatchey, P. Mason, Williams, Ian M., Bracy, Deanna P., Bedenbaugh, Michelle N., Lantier, Louise, Plosa, Erin J., Pozzi, Ambra, Zent, Roy, Wasserman, David H.
Source: American Journal of Physiology: Endocrinology & Metabolism; Dec2024, Vol. 327 Issue 6, pE746-E759, 14p
Subject Terms: CAPILLARY flow, EXERCISE tolerance, INSULIN resistance, GENE knockout, EMBRYOLOGY
Abstract: Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and a β subunit. The integrin β1 (itgβ1) subunit is highly expressed in endothelial cells (ECs). EC itgβ1 is necessary for the formation of capillary networks during embryonic development, and its knockdown in adult mice blunts the reactive hyperemia that manifests during ischemia reperfusion. In this study, we investigated the contribution of EC itgβ1 in microcirculatory function and glucose uptake, with an emphasis on skeletal muscle. We hypothesized that loss of EC itgβ1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating "delivery"-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid the lethality of embryonic gene knockout and the deteriorating health resulting from early postnatal inducible gene deletion. We found that mice with (itgβ1fl/flSCLcre) and without (itgβ1fl/fl) inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction have comparable exercise tolerance and pulmonary and cardiac functions. We quantified microcirculatory hemodynamics using intravital microscopy and the ability of mice to respond to the high metabolic demands of insulin-stimulated muscle using a hyperinsulinemic-euglycemia clamp. We show that itgβ1fl/flSCLcre mice compared with itgβ1fl/fl littermates have 1) deficits in capillary flow rate, flow heterogeneity, and capillary density; 2) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and 3) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgβ1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation. NEW & NOTEWORTHY: The microvasculature is an important site of resistance to muscle glucose uptake. We show that microvasculature integrins determine the exchange of glucose between the circulation and muscle. Specifically, a 30% reduction in the expression of endothelial integrin β1 subunit is sufficient to cause microcirculatory dysfunction and lead to insulin resistance. This emphasizes the importance of endothelial integrins in microcirculatory function and the importance of microcirculatory function for the ability of muscle to consume glucose. [ABSTRACT FROM AUTHOR]
Copyright of American Journal of Physiology: Endocrinology & Metabolism is the property of American Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Endothelial β1-integrins are necessary for microvascular function and glucose uptake.
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  Data: American Journal of Physiology: Endocrinology & Metabolism; Dec2024, Vol. 327 Issue 6, pE746-E759, 14p
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  Data: <searchLink fieldCode="DE" term="%22CAPILLARY+flow%22">CAPILLARY flow</searchLink><br /><searchLink fieldCode="DE" term="%22EXERCISE+tolerance%22">EXERCISE tolerance</searchLink><br /><searchLink fieldCode="DE" term="%22INSULIN+resistance%22">INSULIN resistance</searchLink><br /><searchLink fieldCode="DE" term="%22GENE+knockout%22">GENE knockout</searchLink><br /><searchLink fieldCode="DE" term="%22EMBRYOLOGY%22">EMBRYOLOGY</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and a β subunit. The integrin β1 (itgβ1) subunit is highly expressed in endothelial cells (ECs). EC itgβ1 is necessary for the formation of capillary networks during embryonic development, and its knockdown in adult mice blunts the reactive hyperemia that manifests during ischemia reperfusion. In this study, we investigated the contribution of EC itgβ1 in microcirculatory function and glucose uptake, with an emphasis on skeletal muscle. We hypothesized that loss of EC itgβ1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating "delivery"-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid the lethality of embryonic gene knockout and the deteriorating health resulting from early postnatal inducible gene deletion. We found that mice with (itgβ1<superscript>fl/fl</superscript>SCLcre) and without (itgβ1<superscript>fl/fl</superscript>) inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction have comparable exercise tolerance and pulmonary and cardiac functions. We quantified microcirculatory hemodynamics using intravital microscopy and the ability of mice to respond to the high metabolic demands of insulin-stimulated muscle using a hyperinsulinemic-euglycemia clamp. We show that itgβ1<superscript>fl/fl</superscript>SCLcre mice compared with itgβ1<superscript>fl/fl</superscript> littermates have 1) deficits in capillary flow rate, flow heterogeneity, and capillary density; 2) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and 3) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgβ1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation. NEW & NOTEWORTHY: The microvasculature is an important site of resistance to muscle glucose uptake. We show that microvasculature integrins determine the exchange of glucose between the circulation and muscle. Specifically, a 30% reduction in the expression of endothelial integrin β1 subunit is sufficient to cause microcirculatory dysfunction and lead to insulin resistance. This emphasizes the importance of endothelial integrins in microcirculatory function and the importance of microcirculatory function for the ability of muscle to consume glucose. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of American Journal of Physiology: Endocrinology & Metabolism is the property of American Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1152/ajpendo.00322.2024
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      – Code: eng
        Text: English
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        PageCount: 14
        StartPage: E746
    Subjects:
      – SubjectFull: CAPILLARY flow
        Type: general
      – SubjectFull: EXERCISE tolerance
        Type: general
      – SubjectFull: INSULIN resistance
        Type: general
      – SubjectFull: GENE knockout
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      – SubjectFull: EMBRYOLOGY
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      – TitleFull: Endothelial β1-integrins are necessary for microvascular function and glucose uptake.
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              Text: Dec2024
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