Androgen Action via Testicular Arteriole Smooth Muscle Cells Is Important for Leydig Cell Function, Vasomotion and Testicular Fluid Dynamics

Michelle Welsh,Nina Atanassova,Lee B Smith,Richard M Sharpe,Philippa T K Saunders,Anders Bergh,Sigrid Kilter,Lindsey Moffat,Manuel Tena-Sempere

doi:10.1371/journal.pone.0013632

Abstract

Regulation of blood flow through the testicular microvasculature by vasomotion is thought to be important for normal testis function as it regulates interstitial fluid (IF) dynamics which is an important intra-testicular transport medium. Androgens control vasomotion, but how they exert these effects remains unclear. One possibility is by signalling via androgen receptors (AR) expressed in testicular arteriole smooth muscle cells. To investigate this and determine the overall importance of this mechanism in testis function, we generated a blood vessel smooth muscle cell-specific AR knockout mouse (SMARKO). Gross reproductive development was normal in SMARKO mice but testis weight was reduced in adulthood compared to control littermates; this reduction was not due to any changes in germ cell volume or to deficits in testosterone, LH or FSH concentrations and did not cause infertility. However, seminiferous tubule lumen volume was reduced in adult SMARKO males while interstitial volume was increased, perhaps indicating altered fluid dynamics; this was associated with compensated Leydig cell failure. Vasomotion was impaired in adult SMARKO males, though overall testis blood flow was normal and there was an increase in the overall blood vessel volume per testis in adult SMARKOs. In conclusion, these results indicate that ablating arteriole smooth muscle AR does not grossly alter spermatogenesis or affect male fertility but does subtly impair Leydig cell function and testicular fluid exchange, possibly by locally regulating microvascular blood flow within the testis.

Highlights

Testosterone is essential for normal male fertility, controlling development of the male reproductive system [1] and the later initiation and maintenance of spermatogenesis [2,3]
All SMARKO males were hemizygous for X-linked ARflox while approximately 50% of these males carried the Cre transgene; the ARflox positive Cre negative male littermates were used as controls
We cannot completely rule out any global effect on blood flow affecting the testis, testicular blood flow is believed to be independent of heartbeat and regulated locally [20,21,22] any effect on the aorta is unlikely to have any significant effect on the testis

Summary

Introduction

Testosterone is essential for normal male fertility, controlling development of the male reproductive system [1] and the later initiation and maintenance of spermatogenesis [2,3]. AR is expressed in other testicular cell types including the arteriole smooth muscle cells [6,12], and it has been suggested that androgen signalling via the arterioles may play a role in regulating testicular function and male fertility [12]; how androgens mediate these effects remains unknown. The vascular system forms early in testis development [13,14] and normal testis function depends on the vascular system delivering oxygen, nutrients and hormones into testicular interstitial fluid (IF) and removing waste and secretory products; for example testicular blood flow positively correlates with serum testosterone concentrations [15]. Maintaining normal blood flow through the testicular microvasculature relies on a balance of events at the pre- and post-capillary beds and it has been suggested that steroid hormones may play a role in regulating this [12], but the exact mechanisms remain under explored

Methods

Results

Conclusion