Roles of αv integrins in vascular biology and pulmonary pathology

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Abstract

The five integrins that contain the αv subunit are widely expressed and their expression is tightly regulated. However, most tissues in mice lacking the αv subunit, and thus deficient in all five integrins, develop normally, suggesting that nearly all of the critical steps in development and cellular differentiation can occur in the absence of these integrins. Studies over the past few years have identified highly specialized roles for specific αv integrins in preventing inappropriate vascular growth and in control of vascular permeability. Two members of this family, αvβ6 and αvβ8, play novel roles in activating latent complexes of the growth factor TGFβ (transforming growth factor β). Studies in mice lacking the β6 subunit have identified unexpected roles for αvβ6-mediated TGFβ activation in models of pulmonary and renal fibrosis, acute lung injury and pulmonary emphysema.

Introduction

αv integrins form a subfamily of five members (αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8) that recognize a group of overlapping ligands which generally contain the canonical tripepetide recognition sequence, arginine-glycine-aspartic acid (RGD) [1]. The tight spatial regulation of their expression in most cell types and the results of in vitro functional experiments led many scientists to speculate that αv integrins would play essential roles in cell growth, survival and migration and would be critical for multiple steps in embryonic development. However, inactivation of all five αv integrins (in αv knockout mice) yielded a surprisingly mild phenotype [2]. These mice died during embryonic development or soon after birth as a result of intracranial and/or gastrointestinal hemorrhage. However, there were no other apparent developmental defects, demonstrating that these five integrins are not essential for development, with the limited exception of a small subset of blood vessels.

Although the limited developmental phenotype of mice lacking all αv integrins may have been disappointing to developmental biologists, the availability of live mice lacking individual αv integrins has made possible a series of studies identifying a number of previously unexpected in vivo roles for these integrins. On the basis of studies with these knockout mice and/or with specific integrin antagonists, there is now an emerging view that this subfamily of integrins play important and specific roles in regulating growth and permeability of blood vessels, in regulating tissue inflammation and fibrosis, and in models of several common lung diseases.

This review will highlight recent results that provide new insights into the molecular mechanisms by which distinct αv integrins regulate such diverse in vivo responses.

Section snippets

Roles of αv integrins in vascular development and angiogenesis

The first evidence that a specific integrin might play a critical role in pathologic angiogenesis came from studies of antibody and small-molecule inhibitors of the integrin αvβ3 3., 4.. αvβ3 is induced on endothelial cells of angiogenic vessels, and blocking this integrin prevents angiogenesis in several models. Subsequent evidence suggested that reagents targeting the related integrin αvβ5 were also effective in inhibiting a subset of angiogenic responses specifically dependent on the growth

Role of αvβ5 in regulation of vascular permeability

Although β5 subunit knockout mice do not appear to have abnormalities in vascular development or angiogenesis, these mice do have abnormal vascular responses to the angiogenic growth factor VEGF A. In addition to inducing angiogenesis, VEGF A potently increases vascular permeability (it was initially called ‘vascular permeability factor’). This effect of VEGF A appears to depend on the presence and ligation of αvβ5, since monoclonal antibodies that block αvβ5 inhibit VEGF-induced increases in

αv integrin-mediated activation of latent TGFβ

Transforming growth factor β (TGFβ) belongs to a large family of proteins that is highly conserved across the animal kingdom. In mammals, the TGFβ branch of this family includes three members, TGFβ 1, 2 and 3. Each of these proteins is processed intracellularly and assembled as a complex of two disulfide-linked homodimers formed from the shorter C-terminal fragment (the active cytokine) and the longer N-terminal fragment (termed the latency-associated peptide or LAP). These two homodimers

Roles of αvβ6-mediated TGFβ activation in models of pulmonary disease

Mice lacking the β6 subunit (and thus deficient in αvβ6) have proven to be a useful tool for investigating the range of in vivo functions that depend on αvβ6-mediated TGFβ activation and on the potential contributions of this pathway in models of human disease. As described above, work using these mice has suggested an important role for αvβ6-mediated TGFβ activation in a model of pulmonary fibrosis induced by the anti-cancer drug, bleomycin. A recent study has shown that this pathway also

Conclusions

Studies published over the past two years have clarified the specialized roles of specific αv integrins in the vasculature and in epithelial tissues, including the lung. Two family members, αvβ3 and αvβ5, play important roles in regulating angiogenesis, principally by inducing endothelial cell death when they are not bound to ligand. αvβ5 is also critical for the vascular leak induced by the angiogenic growth factor, VEGF A, and this pathway appears to be important in determining the extent of

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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