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Endocrinology, doi:10.1210/en.2004-0288
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Endocrinology Vol. 145, No. 10 4507-4512
Copyright © 2004 by The Endocrine Society

Direct Regulation of Prostate Blood Flow by Vascular Endothelial Growth Factor and Its Participation in the Androgenic Regulation of Prostate Blood Flow in Vivo

Yasuhiro Shibata, Bunzo Kashiwagi, Seiji Arai, Yoshitatsu Fukabori, Kazuhiro Suzuki, Seijiro Honma and Hidetoshi Yamanaka

Department of Urology (Y.S., B.K., S.A., Y.F., K.S., H.Y.), Graduate School of Medicine, Gunma University, Maebashi 371-8511; and Department of Pharmacological Research (S.H.), Teikoku Hormone Manufacturing, Kawasaki 213-0033, Japan

Address all correspondence and requests for reprints to: Yasuhiro Shibata, Department of Urology, Graduate School of Medicine, Gunma University, 3-39 Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail: yshibata{at}med.gunma-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Previous studies on prostate blood flow regulation have indicated that androgen regulates prostate blood flow. However, the mechanism responsible for this regulation is unknown. In the present study, we focused on the effects of vascular endothelial growth factor (VEGF), a key factor responsible for angiogenesis and androgenic blood flow regulation. We examined in vivo the effect of VEGF on prostate blood flow and its participation in the androgenic regulation of this blood flow using a castrated rat model following subcapsular intraprostatic injection method. We found that VEGF is involved in blood flow regulation with an activity equal to that of dihydrotestosterone (DHT). The effect of VEGF on prostate blood flow was already seen at 30 min after the administration. The elevating effect of DHT on castrated rat prostate blood flow was abolished by coadministration of DHT with neutralizing anti-VEGF antibody. The change in VEGF-A mRNA expression in response to androgen stimulation was examined by double-fluorescent probe quantitative PCR (Taqman PCR). The results showed that androgenic regulation of VEGF gene expression occurred shortly after androgen stimulation. VEGF gene up-regulation was abolished or down-regulated by coadministration of neutralizing anti-VEGF antibody. This is the first report on the importance of VEGF in the androgenic regulation signaling pathway that affects prostate blood flow. Alternative treatment targeted toward anti-VEGF activity as a substitute for ordinary antiandrogenic therapy may be effective against prostate diseases, especially those with androgen-independent and hyperhemorrhagic status.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE PROSTATE GLAND is an androgen-dependent organ, and acute androgen ablation by castration leads to regression of the prostate by apoptosis in the rat (1). The response to androgen ablation is most notable in the ventral lobe (2), and various studies concerning androgenic regulation affecting the prostate were conducted using a rat ventral prostate model (3). Although castration-induced prostate regression is a well-known phenomenon, the precise mechanism responsible for its activity, especially on signal transduction pathways affecting androgenic stimulation, is not fully understood. Recent reports (4, 5) showed that a rapid reduction in prostate blood flow after castration precedes the onset of apoptotic cell death and successive regression of the prostate. These reports support the hypothesis that androgen activity on the prostate may involve primary androgenic regulation of prostate blood flow. We also confirmed the occurrence of early androgenic regulation of prostate blood flow before the volume regression using a castrated-rat ventral prostate model (6). At that time, we showed that there is an early and rapid reduction in prostate blood flow after castration and a prompt increase in blood flow in response to androgen supplement using two different means of blood flow measurement. We had hypothesized the participation of androgens in prostate blood flow regulation as a primary activity.

Although primary androgenic regulation of rat prostate blood flow has been investigated, the mechanism underlying this activity is unclear. In our previous study, androgenic activity affecting rat prostate blood flow accompanied by the regulation of the luminal areas in capillaries was observed by an electron microscope assay (7). Regulation of the vascular luminal area is the result of production of the vasodilator nitric oxide (NO) through the action of endothelial NO synthase, which is released from vascular endothelial cells. Therefore, the involvement of capillary vessels composed of vascular endothelial cells is important in the androgenic regulation of prostate blood flow. However, the direct genomic activity of androgen on vascular endothelial cells is minimal because they do not express the androgen receptor (AR) (8). As a result, androgen stimulation signaling is likely transmitted through other AR-positive cells by transmitters or is directly transmitted to vascular endothelial cells by AR-independent, nongenomic means.

Vascular endothelial growth factor (VEGF) is expressed in the prostate and possesses angiogenic activity, increases vascular permeability, and may regulate organ blood flow. Furthermore, VEGF acts as an androgen-dependent factor that is down-regulated by androgen ablation and up-regulated by testosterone stimulation (9, 10, 11). These characteristics are suitable for a transmitter of androgenic regulation of prostate blood flow.

To evaluate the participation of VEGF in prostate blood flow regulation, especially in the androgenic regulation of prostate blood flow, we investigated the activity of the VEGF in vivo using a newly developed subcapsular intraprostatic injection technique in a castrated-rat model.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Ten-week-old male Wistar strain rats were purchased from Japan SLC Co. (Shizuoka, Japan). The animals were housed under controlled conditions and given water and food pellets ad libitum for at least 1 wk before and during the experiments. The rats were randomly divided into groups and all operations were performed under ip injection anesthesia of pentobarbiturate (50 mg/kg body weight). All surgical and experimental procedures were approved and conducted in accordance with the guidelines of the Institutional Laboratory Animal Care and Use Committee of Gunma University.

Chemicals
Testosterone and dihydrotestosterone (DHT) were purchased from Sigma Chemical Co. (St. Louis, MO), and recombinant VEGF and antihuman VEGF antibody (monoclonal) was purchased from PeproTech Inc. (Rocky Hill, NJ). Testosterone and DHT were dissolved in 2% Tween 80-saline. VEGF and antihuman VEGF antibody were dissolved in saline. 51[Cr]-labeled microspheres (15 µm diameter, 740-3330 MBq/g) were purchased from NEN Life Science Products, Inc. (Boston, MA).

Instruments
Radioactivity was measured using an Auto Well {gamma} System ARC-1000M scintillation counter (Aloka Co. Ltd., Tokyo, Japan). Laser speckle blood flowmeter ALF21R with the OP type ALF probe (Advance Co., Tokyo, Japan) was used for the study. Real-time quantitative PCR was performed using an iCycler iQ real-time PCR detection system (Bio-Rad Laboratories, Hercules, CA).

Animal treatments and experimental designs
Measurement of relative prostate blood flow after the administration of androgen or VEGF to castrated rats.
A 1.5-cm incision was made in the mid-lower abdomen of 18-h castrated rats, and the ventral prostate was exposed by gently holding back the surrounding tissues. Then DHT (100 ng) or VEGF (500 ng and 2 µg), adjusted to a volume of 25 µl, was directly injected into the subcapsular ventral prostate using a 27-gauge needle. Relative prostate blood flow was measured 6 h after the injection (24 h after castration). Intraprostate saline-injected rats were simultaneously assayed as negative controls. Each group consisted of six to seven rats.

Measurement of relative prostate blood flow after the administration of androgen in combination with VEGF neutralizing antibody (anti-VEGF antibody).
The rats were administered DHT (100 ng) in combination with anti-VEGF antibody (10 µg) directly into the subcapsular ventral prostate as described above 18 h after castration. Relative prostate blood flow was measured 6 h after the injection (24 h after castration). Intraprostate saline-injected rats and normal rats subjected to anti-VEGF antibody intraprostate injection (6 h before the measurement) were simultaneously assayed as controls. Each group consisted of six to seven rats.

Evaluation of time-course effect and dose response of VEGF on prostate blood flow.
Five hundred nanograms of VEGF were injected locally into the subcapsular ventral prostate, and the prostate blood flow was measured at 0, 0.5, 1, 2, 3, and 4 h after the injection by laser speckle blood flowmeter. The time-course evaluation of VEGF on prostate blood flow was examined for 18-h and 3-d castrated rats (n = 4). The time-course effect of local prostate VEGF injection on renal blood flow was also examined in 18-h castrated rats.

For the dose-response study, VEGF was injected locally into the subcapsular ventral prostate in doses of 0, 1, 10, 100, and 500 ng. The prostate blood flow was evaluated by laser speckle blood flowmeter at 30 min after the injection.

Quantitative analysis of VEGF mRNA expression after the administration of DHT, DHT in combination with anti-VEGF antibody, or VEGF in the castrated rat prostate.
Rats were castrated for 2 d to allow the drastic endocrine environmental change resulting from androgen ablation to settle and abolish the effect of endogenous androgen. Then DHT (100 ng) was directly injected into their prostates as described above with or without anti-VEGF antibody (10 µg). The effect of VEGF (500 ng) injection was also examined. Their prostates were excised 30 min and 3 h after the injection and immediately frozen in liquid nitrogen. Prostate tissues were stored at –70 C until analysis of gene expression levels by real-time quantitative PCR. Two day-castrated and normal rats treated with intraprostate saline injection were simultaneously assayed as negative and positive controls, respectively. Each group consisted of three rats.

Evaluation of relative blood flow to the prostate by the radioactive microsphere injection technique
The blood supply to the prostate was examined by evaluating the uptake of intraarterially injected radioactive microspheres. The uptake of microspheres in the prostate was reported to parallel the organ blood flow (12, 13). Fifteen microcuries of radioactive microspheres suspended in 0.35 ml saline containing 0.01% Tween-80 were injected via a catheter inserted into the left common carotid artery. The ventral prostate and unilateral kidney were excised and weighed 2.5 min after the injection, and their radioactivities were measured using a {gamma}-scintillation counter. Prostate blood flow was corrected for using the radioactive uptake of the kidney, an androgen-independent organ to eliminate minor differences that occurred in each animal during the procedure, thus allowing it to be expressed as relative prostate blood flow. The final relative prostate blood flow to the ventral prostate was calculated using the formula: radioactivity of the ventral prostate per milligram of tissue/radioactivity of the kidney per milligram of tissue. The final relative blood flow was expressed as a ratio to that of the intact control group in each experiment. Details of the microsphere injection technique were previously described (6).

Blood flow measurement by laser speckle blood flowmetry
Each rat was fixed in a supine position and operated on by a midabdominal incision. Then ventral lobes of the prostate were exposed carefully, and the probe tip of the laser speckle blood flowmeter was gently placed on the organ. The probe was set still for 30 sec to stabilize measured blood flow values on the display, and the value was recorded. The measurement was repeated three times on randomly selected organ surfaces, and then the values were averaged. Blood flow of the kidney was measured similar to the method for the prostate. The detail of laser speckle blood flowmetry was reported previously (6).

Quantitative mRNA analysis of VEGF-A
Total RNA was extracted from the frozen prostates with TRIzol reagent (Life Technologies Oriental Inc., Tokyo, Japan) according to the manufacturer’s instructions. First-strand cDNA from the RNA template was generated with Ready-To-Go You-Prime-First-Strand Beads (Pharmacia Biotech K.K., Tokyo, Japan). Sample cDNAs were amplified in a model 7700 sequence detector (PE Applied Biosystems, PerkinElmer Japan, Chiba, Japan) using the forward and reverse primers and dual-labeled fluorogenic probe (TaqMan probe) with a TaqMan PCR reagent kit. The sequence of primers and probe for VEGF-A detection used in the study were 5'-TCCTGTGTGCCCCTAATGC-3', 5'-GCACTCCAGGGCTTCATCA-3' and 5'-FAM-TGTGCGGGCTGCTGCA-TAMRA-3'. The PCR mixture with 2.5 mM MgCl2 was heated to 60 C in the annealing step and amplified for 50 cycles. The known concentrations of serially diluted VEGF-A cDNA generated by PCR were employed as a standard for quantification of the sample cDNAs. To determine the copy number of glyceraldehyde phosphate dehydrogenase (GAPDH) mRNA, TaqMan GAPDH control reagents (PE Applied Biosystems) were used according to the manufacturer’s instructions. The cDNA copy numbers of target genes were normalized against the GAPDH result for the same sample volume.

Statistical analysis
Statistical significance was determined by the Mann-Whitney U test using StatView J-4.51.2 (Abacus Concepts, Inc., Berkeley, CA) on a Macintosh computer (Apple Computer, Inc., Cupertino, CA). Differences were considered significant when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effect of DHT or VEGF on prostate blood flow
Relative prostate blood flow significantly increased up to a normal level after the local administration of DHT. Intraprostate administration of VEGF also increased relative prostate blood flow to the extent of DHT administration. The effect of VEGF was observed for doses at 500 ng and 2 µg (Fig. 1).

Effect of anti-VEGF antibody on the androgenic regulation of prostate blood flow
The blood flow-increasing effect of DHT on the prostate of castrated rats was completely inhibited by coadministration of anti-VEGF antibody (Fig. 2Go).



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  		FIG. 2. Effect of anti-VEGF antibody on androgen-induced elevation in prostate blood flow in castrated rats. The elevating effect of DHT on prostate blood flow was completely inhibited by coadministration of anti-VEGF antibody. Each column represents the mean of the ratio of relative blood flow to the normal control, and the bars indicate the SE. Cx, Castration; VEGF Ab, anti-VEGF antibody. *, Significantly different from castrated rats (P < 0.05).

 
The time-course change and dose effect in prostate blood flow after the local administration of VEGF
Prostate blood flow was increased significantly 30 min after the local administration of VEGF in both 18-h and 3-d castrated rats (Fig. 3Go). The increasing effect of VEGF on prostate blood flow was continued to 4 h after the administration. The local intraprostatic administration of VEGF did not affect renal blood flow in 3-d castrated rats.



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  		FIG. 3. The time-course change in prostate blood flow after administration of VEGF. Prostate blood flow was increased significantly from 30 min after the administration of VEGF both in 18-h and 3-d castrated rats. The renal blood flow in 3-d castrated rats was not increased by local prostate administration of VEGF. Prostate 18 h, Prostate blood flow change in 18-h castrated rats; prostate 3d, prostate blood flow change in 3-d castrated rats; kidney 3d, renal blood flow change in 3-d castrated rats. *, Significantly different from preadministration of VEGF (P < 0.05).

 
There was positive correlation between the dose of VEGF and blood flow-increasing effect from 1 to 100 ng (Fig. 4Go).



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  		FIG. 4. The dose effect of VEGF on prostate blood flow. There was positive correlation between dose of VEGF and prostate blood flow.

 
Changes in gene expression of VEGF after the administration of DHT or DHT in combination with anti-VEGF antibody or VEGF in the castrated rat prostate
VEGF-A gene expression in the prostate was significantly up-regulated 30 min after DHT injection. Up-regulation was maintained 3 h after DHT injection but was completely suppressed or even down-regulated (not significant) by coadministration of anti-VEGF antibody. Intraprostatic VEGF administration significantly up-regulated VEGF gene expression itself (Fig. 5Go).



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  		FIG. 5. Changes in gene expression of VEGF after the administration of DHT, DHT in combination with anti-VEGF antibody, or VEGF in the castrated rat prostate. VEGF-A gene expression of was significantly up-regulated after the intraprostatic administration of DHT or VEGF. Up-regulation of the VEGF-A gene in the DHT-administered rat was completely suppressed by coadministration of anti-VEGF antibody. Each column represents the mean of the ratio of gene expression to the control, and the bars indicate the SE. VEGF Ab, Anti-VEGF antibody. *, Significantly different from castrated rats (P < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study show that VEGF directly affects prostate blood flow in dose-dependent manner. The effect of VEGF on prostate blood flow regulation was equal to that of DHT stimulation, which implies that it is a mediator of the signal transduction pathway involved in prostate blood flow regulation. Furthermore, the effect of VEGF on prostate blood flow was already observed at 30 min after the administration, suggesting VEGF as a mediator located considerably downstream of the signal transduction pathway for prostate blood flow regulation. Our subcapsular intraprostatic direct injection technique made it possible to locally examine the function of test agents in the target organ in vivo. This procedure can be performed through a small lower abdominal incision with minimal influence on the prostate and surrounding tissues. The fact that intraprostatic injection of VEGF did not affect the renal blood flow meant the procedure as reasonable for examining the effect of test agents on the local prostate blood flow. The main function of VEGF is thought to be the promotion of angiogenesis along with inducing increases in vascular permeability (14). This is the first study to examine the direct effect of VEGF on the prostate blood flow regulation.

The participation of VEGF in the androgenic regulation of prostate blood flow was examined by blocking the effect of VEGF using neutralizing anti-VEGF antibody. The blood flow-enhancing effect of DHT on the prostate was abolished by VEGF neutralizing anti-VEGF antibody, showing that VEGF plays role in the androgenic regulation of prostate blood flow. Reports on the androgenic regulation of VEGF (9, 10, 11) support our observation that VEGF participates in the androgenic regulation of prostate blood flow.

Prostate blood flow rapidly decreases after castration (4), suggesting the occurrence of an early response in the signal transduction pathway. Therefore, we examined the change in VEGF-A gene expression in response to androgen stimulation by the Taqman quantitative PCR method. VEGF-A gene expression was up-regulated in response to androgen stimulation, showing that it acts as an androgenic-regulated factor. Furthermore, the prompt response of VEGF-A up-regulation (within 30 min of androgen stimulation) suggests that VEGF-A regulation might be directly controlled by androgen. VEGF is abundantly localized in epithelial and interglandular stromal cells of the prostate (15). These cells bear the androgen receptor so that VEGF secreted by them may act as a second messenger upstream of the signal transduction pathway responsible for the androgenic regulation of prostate blood flow.

Up-regulation of the VEGF-A gene due to VEGF administration suggests that paracrine/autocrine regulation occurs. Down-regulation of the VEGF-A gene due to coadministration with neutralizing anti-VEGF antibody also supports this hypothesis.

The mechanism governing the prostate blood flow regulation signal transduction pathway downstream of VEGF secretion is unknown. However, as a result of our previous study on morphological changes in capillaries resulting from androgenic regulation (6, 16), it appears to be accompanied by control of the luminal area of capillaries in the prostate. Because capillaries are composed of vascular endothelial cells that do not express the androgen receptor (8), the direct regulation of capillaries by androgen is minimal. Therefore, other regulating factors must be involved. Androgen-regulated factors including NO (17), prostaglandins (18), and angiotensins (19) may be active in the signal transduction pathway.

In conclusion, VEGF signaling is involved in the androgenic regulation of prostate blood flow. Alternative treatments targeted toward anti-VEGF action as substitutes for ordinary antiandrogenic therapy may be effective against prostate diseases, especially those with androgen-independent and hyperhemorrhagic status.



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  		FIG. 1. Relative prostate blood flow after the injection of DHT and VEGF into castrated rats. The blood flow of castrated rats returned to normal after the local administration of DHT or VEGF. VEGF was tested at two doses. Each column represents the mean of the ratio of relative blood flow to the control, and the bars indicate the SE. Cx, Castration; VEGF low, 500 ng; VEGF high, 2 µg. *, Significantly different from castrated rats (P < 0.05).

 

   Footnotes
 
Abbreviations: AR, Androgen receptor; DHT, dihydrotestosterone; GAPDH, glyceraldehyde phosphate dehydrogenase; NO, nitric oxide; VEGF, vascular endothelial growth factor.

Received March 5, 2004.

Accepted for publication June 22, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  17. Marin R, Escrig A, Abreu P, Mas M 1999 Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol Reprod 61:1012–1016[Abstract/Free Full Text]
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