Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1α

Abstract

Testosterone-stimulated growth of the ventral prostate (VP) in castrated rats is preceded by angiogenesis, but the mechanisms coordinating vascular and tissue growth are unknown. Adult rats were castrated and some treated with testosterone. Tissue hypoxia was studied morphologically using the hypoxia marker pimonidazole (Hypoxyprobe), hypoxia-inducible factor-1 (HIF-1) a, vascular endothelial growth factor (VEGF), and carbonicanhydrase 9 (CA-9) levels by western blotting and quantitative RT-PCR. In the intact untreated prostate, most glands were unstained by the hypoxia marker but already 1 day after castration most epithelial cells in the VP were stained. Seven days after castration prostate glands were apparently normoxic again, and HIF-1a, VEGF, and CA-9 were decreased. Treatment of 7-day castrated rats with testosterone resulted in increased epithelial hypoxyprobe staining and increased HIF-1a, VEGF, and CA-9 levels. The transient increase in tissue hypoxia after testosterone treatment is probably caused by a temporary mismatch between oxygen consumption and supply. Treatment of prostate epithelial cells in vitro under normoxic conditions also increased HIF-1a, and this could be blocked if epidermal growth factor receptor (EGFR) signaling was blocked with gefitinib. In vivo gefitinib could, however, not block the testosterone induced increase in HIF-1a. Testosterone may thus induce HIF1a and its downstream angiogenesis promoting genes by at least two mechanisms, hypoxia and EGFR signaling. Transient epithelial cell hypoxia could by rapidly increasing HIF-1a and VEGF be an essential coordinator of testosterone-stimulated vascular and glandular growth.

Androgen Receptor Promotes Sex-Independent Angiogenesis in Response to Ischemia and Is Required for Activation of Vascular Endothelial Growth Factor Receptor Signaling

“…However, the observation that ischemic lims from ARKO mice exhibited marked edema and a dusky red-colored skin appearance on day 1 after surgery are consistent with exaggerated ischemia in the operated limbs of ARKO mice. Since previous studies showed that castration rapidly reduces blood flow to the rat ventral prostate gland with acceleration of epithelial cellular apoptosis and tissue hypoxia 53, 54 and since we have reported that AR deficiency reduces nitric oxide bioavailability 22 , lack of androgen action may lead to prominent tissue hypoxia due to circulatory insufficiency. Although further investigations are needed to clarify this issue, we speculate that the enhanced Hif1a and Vegfa expression levels reflect a more severe acute ischemic condition in ARKO mice than in WT mice.…”

Vitamin C supplementation prevents testosterone-induced hyperplasia of rat prostate by down-regulating HIF-1α

“…Therefore, if any of these co-factors is limited, HIF-1α becomes stabilized and activated regardless of oxygen level. In addition, to this hydroxylation process, HIF-1α is known to be induced by some growth factors which accelerate the de novo synthesis of HIF-1α protein [9,10], and, similarly, testosterone has also been recently reported to stimulate HIF-1α synthesis even under normoxic conditions [11,12].…”

Methylseleninic acid downregulates hypoxia‐inducible factor‐1α in invasive prostate cancer

“…33 Furthermore, transient epithelial cell hypoxia has been shown to rapidly increase HIF-1a and its downstream targets such as VEGF in rat prostate tumors. 34 Our investigation tested the hypothesis that MSeA inhibits HIF1a and its downstream targets involved in growth of invasive prostate cancer under hypoxic conditions.…”