Integrin αvβ8-Mediated Activation of Transforming Growth Factor-β by Perivascular Astrocytes

Abstract

Brain hemorrhage is a severe complication of both neoplastic and nonneoplastic brain disease. Mice deficient in the alpha(v)beta8 integrin display defective brain vessel formation resulting in hemorrhage and perinatal death, but the mechanism of brain hemorrhage is unknown. Because the alpha(v)beta8 integrin is expressed by astrocytes and not expressed by endothelium, paracrine interactions between astrocytes and endothelial cells could contribute to the maintenance of brain vessel integrity. We have investigated the mechanisms underlying astrocytic-endothelial paracrine signaling and have found that integrin-mediated activation of transforming growth factor (TGF)-beta by astrocytes influences endothelial cell function. Thus, we identified the integrin alpha(v)beta8 in human perivascular glial cell processes surrounding developing blood vessels. Human astrocytic alpha(v)beta8 was a major cell surface receptor for latent TGF-beta, and alpha(v)beta8-dependent activation of TGF-beta was the major mechanism of TGF-beta activation in primary cultures of astrocytes or freshly dissociated fetal brain cells. This activation of TGF-beta was sufficient to inhibit endothelial migration in fibrin gels and to alter expression of genes affecting proteolytic and angiogenic pathways. Taken together, our data suggest that astrocytic alpha(v)beta8 acts as a central regulator of brain vessel homeostasis through regulation of TGF-beta activation and expression of TGF-beta-responsive genes that promote vessel differentiation and stabilization, most notably plasminogen activator inhibitor-1 and thrombospondin-1.

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

“…The discrepancy between these 2 studies likely represents inherent cell type-specific differences between airway and dermal fibroblasts. For instance, we have found that unlike human airway fibroblasts, human dermal fibroblasts do not express α v β 8 (53). However, it is likely that there are other differences between airway epithelial cells and keratinocytes in the cofactors that they secrete that can modify fibroblast responses to IL-1β.…”

An interaction between αvβ8 integrin and Band 4.1B via a highly conserved region of the Band 4.1 C-terminal domain

“…Glial endfeet are closely juxtaposed to most blood vessels in the CNS. Indeed, while this manuscript was under review, immunoelectron microscopy localized ␣v␤8 to perivascular glial endfeet (21). In the adult brain, Band 4.1N, but not Band 4.1B, was also expressed in a perivascular pattern (Fig.…”

Transcription of the Transforming Growth Factor β Activating Integrin β8 Subunit Is Regulated by SP3, AP-1, and the p38 Pathway

“…The integrin ␣v␤8 is of particular interest because it is the only ␣v subunit-containing integrin that has been shown to be essential for development (8 -14). The integrin ␤8 subunit is expressed in various epithelial (squamous mucosa, airway epithelium, renal tubular epithelium, and neuroepithelium) (1,(15)(16)(17), mesenchymal (fibroblasts, kidney mesengial cells, and astrocytes) (18,19), and select immune cell types (splenocytes, CD44…”