Cellular responses to changes in available oxygen (O2) levels are essential for normal development and physiology, and play a crucial role in disease. Hypoxia-inducible factors (HIFs) participate in these responses by stimulating the expression of genes involved in glycolysis, hematopoiesis, cell motility, and angiogenesis, all of which contribute to hypoxic adaptations. HIFs are heterodimeric transcription factors consisting of 1 (HIF-11 or HIF-21) and 2 (ARNT) subunits. Much attention has been focused on the ubiquitously expressed HIF-11 factor. However, the related protein HIF-21 clearly plays an important, as yet largely undetermined role in hypoxic adaptations. HIF-21 is highly expressed in endothelial cells (ECs) and regulates the expression of multiple genes that control angiogenesis such as VEGF, Tie2, and adrenomedullin. Moreover, HIF-21 preferentially regulates hypoxic VEGF expression in multiple cell types. Previous reports describe the effects of ablating HIF-11 in ECs, while little is known about HIF-21 function in these cells. To fully understand the complex role of hypoxia in controlling angiogenesis, particularly in response to pathological conditions such as tissue ischemia and solid tumors, it is important to establish the mechanisms by which HIF-21 functions in ECs and proangiogenic bone marrow-derived cells. This proposal will test the following hypothesis: HIF-21 plays critical and unique roles in regulating angiogenic responses to hypoxia, particularly during adult neovascularization. To test this hypothesis, we will (1) determine the role of HIF-21 in vascular EC function in vitro, (2) define the role of HIF-21 in ECs in vivo, and (3) determine the effects of HIF-21 ablation in the recruitment and function of proangiogenic bone marrow derived-monocytes (BMDMs). The proposed experiments are timely, in that recent reports suggest that HIF-21 (but not HIF-11) is critical to the progression of specific malignancies such as renal clear cell carcinoma, small cell lung carcinoma, neuroblastoma, and astrocytoma. The overall goal of these studies is to delineate how HIF-11 and HIF-21 differentially regulate hypoxic gene induction and how this contributes to angiogenesis, especially in adult pathophysiological settings. Project Narrative:Oxygen is essential for most life forms on earth. Therefore, responses to changes in oxygen availability are critical for development, physiology, and diseases such as the growth of solid tumors or tissue ischemia. Oxygen sensitive hypoxia-inducible factors participate in these responses and have been implicated in the growth of tumors such as renal clear cell carcinoma, small cell lung carcinoma, colon carcinoma, and neuroblastoma. This project will provide fundamental insights into how these factors regulate blood vessel growth in diseases and identify new therapeutic targets to treat cancer, stroke, and heart attack patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066310-13
Application #
8286244
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Thomas, John
Project Start
2000-03-15
Project End
2013-07-31
Budget Start
2012-07-01
Budget End
2013-07-31
Support Year
13
Fiscal Year
2012
Total Cost
$382,126
Indirect Cost
$134,626
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Shay, Jessica E S; Imtiyaz, Hongxia Z; Sivanand, Sharanya et al. (2014) Inhibition of hypoxia-inducible factors limits tumor progression in a mouse model of colorectal cancer. Carcinogenesis 35:1067-77
Thompson, A A Roger; Elks, Philip M; Marriott, Helen M et al. (2014) Hypoxia-inducible factor 2* regulates key neutrophil functions in humans, mice, and zebrafish. Blood 123:366-76
Li, Min; Bertout, Jessica A; Ratcliffe, Sarah J et al. (2010) Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension. Anesthesiology 113:845-58
Hickey, Michele M; Richardson, Theresa; Wang, Tao et al. (2010) The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest 120:827-39
Lee, C M; Hickey, M M; Sanford, C A et al. (2009) VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene 28:1694-705
Mack, Fiona A; Rathmell, W Kimryn; Arsham, Andrew M et al. (2003) Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 3:75-88