Adenosine A2A receptor is a unique angiogenic target of HIF-2alpha in pulmonary endothelial cells.
نویسندگان
چکیده
Hypoxia, through the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha (HIFs), induces angiogenesis by up-regulating a common set of angiogenic cytokines. Unlike HIF-1alpha, which regulates a unique set of genes, most genes regulated by HIF-2alpha overlap with those induced by HIF-1alpha. Thus, the unique contribution of HIF-2alpha remains largely obscure. By using adenoviral mutant HIF-1alpha and adenoviral mutant HIF-2alpha constructs, where the HIFs are transcriptionally active under normoxic conditions, we show that HIF-2alpha but not HIF-1alpha regulates adenosine A(2A) receptor in primary cultures of human lung endothelial cells. Further, siRNA knockdown of HIF-2alpha completely inhibits hypoxic induction of A(2A) receptor. Promoter studies show a 2.5-fold induction of luciferase activity with HIF-2alpha cotransfection. Analysis of the A(2A) receptor gene promoter revealed a hypoxia-responsive element in the region between -704 and -595 upstream of the transcription start site. By using a ChIP assay, we demonstrate that HIF-2alpha binding to this region is specific. In addition, we demonstrate that A(2A) receptor has angiogenic potential, as assessed by increases in cell proliferation, cell migration, and tube formation. Additional data show increased expression of A(2A) receptor in human lung tumor cancer samples relative to adjacent normal lung tissue. These data also demonstrate that A(2A) receptor is regulated by hypoxia and HIF-2alpha in human lung endothelial cells but not in mouse-derived endothelial cells.
منابع مشابه
Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype.
We previously reported that adenosine A2B receptor activation stimulates angiogenesis. Because hypoxia is a potent stimulus for the release of both adenosine and angiogenic factors, we tested the hypothesis that hypoxia alters the expression of adenosine receptors toward an "angiogenic" phenotype. We used human umbilical vein endothelial cells (HUVECs) and bronchial smooth muscle cells (BSMCs) ...
متن کاملHypoxia Modulates Adenosine Receptors in Human Endothelial and Smooth Muscle Cells
We previously reported that adenosine A2B receptor activation stimulates angiogenesis. Because hypoxia is a potent stimulus for the release of both adenosine and angiogenic factors, we tested the hypothesis that hypoxia alters the expression of adenosine receptors toward an “angiogenic” phenotype. We used human umbilical vein endothelial cells (HUVECs) and bronchial smooth muscle cells (BSMCs) ...
متن کاملHypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha.
Hypoxia-induced mitogenic factor (HIMF), also called FIZZ1 or RELMalpha, was a newly found cytokine. Hypoxia caused robust HIMF induction in the lung, and HIMF has potent pulmonary vasoconstrictive, proliferative, and angiogenic properties. To investigate the role of HIMF in lung development, we determined its spatial and temporal expression. From embryonic day (E)16 to postnatal day (P)28, HIM...
متن کاملUpregulated hypoxia inducible factor-1α and -2α pathway in rheumatoid arthritis and osteoarthritis
The pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA) remains obscure, although angiogenesis appears to play an important role. We recently confirmed an overexpression of two angiogenic factors, namely vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF), by the lining and stromal cells of the synovium in both conditions. Becaus...
متن کاملAdenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages.
Adenosine released by cells in injurious or hypoxic environments has tissue-protecting and anti-inflammatory effects, which are also a result of modulation of macrophage functions, such as vascular endothelial growth factor (VEGF) production. As VEGF is a well-known target of hypoxia-inducible factor 1 (HIF-1), we hypothesized that adenosine may activate HIF-1 directly. Our studies using subtyp...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 106 26 شماره
صفحات -
تاریخ انتشار 2009