Endoglin Expression Is Regulated by Transcriptional Cooperation between the Hypoxia and Transforming Growth Factor-β Pathways

Abstract

Endoglin is a transforming growth factor-␤ (TGF-␤) co-receptor expressed mainly on endothelial cells and involved in cardiovascular development, angiogenesis, and vascular remodeling. This is illustrated by the fact that mutations in the endoglin gene give rise to hereditary hemorrhagic telangiectasia type 1, a dominant vascular disease with clinical manifestations that originate by a mechanism of haploinsufficiency. Thus, studies on the regulated expression of endoglin are crucial to devising therapeutic strategies for hereditary hemorrhagic telangiectasia type 1. Endoglin is highly expressed in the neovasculature associated with hypoxia such as ischemic tissues and tumors, but the molecular mechanism of this up-regulation is unknown. Here, we have investigated the possible regulation of endoglin expression by hypoxia. Surface protein, transcript, and promoter activity levels of endoglin were found to be up-regulated by hypoxia, indicating that the regulation takes place at the transcriptional level. A hypoxia-responsive element downstream of the main transcription start site of the endoglin gene was functionally characterized. Whereas hypoxia alone moderately stimulated endoglin transcription, addition of TGF-␤ under hypoxic conditions resulted in transcriptional cooperation between both signaling pathways, leading to marked stimulation of endoglin expression. Because basal endoglin transcription is sustained by Sp1, and TGF-␤ and hypoxia signaling pathways are mediated by Smad proteins and hypoxia-inducible factor-1 (HIF-1), respectively, the involvement of these transcription factors was analyzed. Functional and co-immunoprecipitation experiments demonstrated the existence of a multiprotein complex (Sp1⅐Smad3⅐HIF-1) on the endoglin promoter, mediating the cooperation between the hypoxia and TGF-␤ pathways. Within this multiprotein complex, Smad3 appears to function not only as a coactivator factor, but also as an adaptor between HIF-1 and Sp1. We propose that basal endoglin transcription (highly dependent on Sp1) may switch from a constitutive to an inducible state through Sp1 interaction with HIF-1 and Smad transcription factors, induced by hypoxia and TGF-␤, respectively.

The role of bone morphogenetic proteins in myeloma cell survival

“…ALK5 (TGFBR1) is expressed in myeloma cells and is capable of being activated in response to TGF-β. [39] Both myeloma cell lines and primary cells were shown to express TGF-β mRNA and active protein, [40,41] however it was also reported that myeloma cells do not produce active TGF- Expression of the other type 3 receptor, endoglin, is induced by TGF-β and hypoxia, [44,45] and increased levels of soluble endoglin in myeloma patients were associated with advanced disease and tumor growth. [46,47] Membrane-bound endoglin is found on some myeloma cell lines, but lack on others.…”

Identification of Endoglin in Rat Hepatic Stellate Cells

“…One potential factor that is able to increase the expression of endoglin is the receptor ligand TGF-␤ itself. In endothelial cells, monocytic cells, human mesangial cells, and cultured cell lines, TGF-␤ is able to upregulate promoter activity and endoglin expression (75)(76)(77)(78)(79). Because it is well documented that activated HSC and MFB produce large amounts of TGF-␤ (52, 80), endoglin expression could be maintained during transdifferentiation by persistent autocrine stimulation by TGF-␤.…”

Endothelial dysfunction and hypertension in obstructive sleep apnea – Is it due to intermittent hypoxia?

“…17 These angiogenesis inhibitors are released under inflammatory state. 18,19 These circulating proteins have been shown to have pathogenetic roles in hypertension in preeclampsia, 20 in human chronic kidney disease, 21 coronary artery disease 22 and in animal models of hypertension. 23,24 However, none of the studies have examined the relationship between endothelial dysfunction and hypertension in relationship to hypoxia exposure in OSA patients.…”