Abstract
Endoglin is a type III TGFβ auxiliary receptor that is upregulated in endothelial cells during angiogenesis and, when mutated in humans, results in the vascular disease hereditary hemorrhagic telangiectasia (HHT). Though endoglin has been implicated in cell adhesion, the underlying molecular mechanisms are still poorly understood. Here we show endoglin expression in endothelial cells regulates subcellular localization of zyxin in focal adhesions in response to BMP9. RNA knockdown of endoglin resulted in mislocalization of zyxin and altered formation of focal adhesions. The mechanotransduction role of focal adhesions and their ability to transmit regulatory signals through binding of the extracellular matrix are altered by endoglin deficiency. BMP/TGFβ transcription factors, SMADs, and zyxin have recently been implicated in a newly emerging signaling cascade, the Hippo pathway. The Hippo transcription coactivator, YAP1 (yes-associated protein 1), has been suggested to play a crucial role in mechanotransduction and cell-cell contact. Identification of BMP9-dependent nuclear localization of YAP1 in response to endoglin expression suggests a mechanism of crosstalk between the two pathways. Suppression of endoglin and YAP1 alters BMP9-dependent expression of YAP1 target genes CCN1 (cysteine-rich 61, CYR61) and CCN2 (connective tissue growth factor, CTGF) as well as the chemokine CCL2 (monocyte chemotactic protein 1, MCP-1). These results suggest a coordinate effect of endoglin deficiency on cell matrix remodeling and local inflammatory responses. Identification of a direct link between the Hippo pathway and endoglin may reveal novel mechanisms in the etiology of HHT.
Highlights
Hereditary hemorrhagic telangiectasia (HHT) is a progressive vascular disease that affects as many as 1 in 5,000 people [1, 2]
Annexin A2, a membrane protein that is present in the cytosol, focal adhesion fraction and extracellular matrix fractions [66], provides both a normalization control between samples within each subfraction and, along with β-actin, an indication of enrichment for focal adhesion proteins. These results suggest that BMP9-dependent localization of zyxin in sites of focal adhesion formation in Human umbilical vein endothelial cells (HUVECs) is associated with increased endoglin levels, consistent with studies indicating that endoglin and zyxin are interacting proteins [43, 44]
Though zyxin did not appear decreased in the shNT or endoglin knockdown (shENG) HUVECs as anticipated, these results suggest a role for BMP9 cooperation with endoglin in the localization of zyxin in endothelial cells, and support the idea that reduced zyxin in the cell-cell and ECMcell junctions in the eng+/- mouse lungs potentially renders vessels more vulnerable to arteriovenous malformations (AVMs) formation
Summary
Hereditary hemorrhagic telangiectasia (HHT) is a progressive vascular disease that affects as many as 1 in 5,000 people [1, 2]. The authors thank Ms Sarah Coreau for help in the preparation of this manuscript
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