To examine the role of androgen receptor (AR) in Sertoli cells (SC), we used a SC-specific AR knockout (S-AR-/y) mouse to further evaluate the chronological changes of seminiferous tubules and the molecular mechanisms of SC androgen/AR signals on spermatogenesis. Testes morphology began changing as early as postnatal day (PD) 10.5 in wild-type (WT), but not in S-AR-/y mice. After puberty (PD 50), the SC nuclei of WT testes migrated to the basal area of the seminiferous epithelium; however, in S-AR-/y testes, SC nuclei were disarranged and dislocated. Results from electron microscopy further showed an obvious duplication of basal lamina of the seminiferous epithelium in S-AR-/y testes at PD 50 compared with WT testes. Using quantitative RT-PCR analyses, the expression of SC gene profiles were compared in PD 10.5 testes. In S-AR-/y testes, the expression levels of 1) vimentin were significantly increased and laminin alpha5 was significantly decreased in PD 10.5, which contributed to functional defects in cytoskeletons and production of the basement membrane component of SC leading to cell morphology deterioration and thus affecting the integrity of seminiferous epithelium; 2) claudin-11, occludin, and gelsolin were significantly decreased in PD 10.5, which contributed to defects in intact junctional complex formation of SC leading to impairment of the integrity of the blood-testis barrier; 3) calcium channel, voltage-dependent, P/Q-type, alpha1A subunit; tissue-type plasminogen activator; transferrin; and epidermal fatty-acid-binding protein were significantly decreased in PD 10.5, which contributed to functional defects in production and/or secretion of specific proteases, transport proteins, and paracrine factors of SC, leading to impairment of its germ cells' nursery functions.

Androgens and the androgen receptor (AR) play important roles in the testes. Previously we have shown that male total AR knockout (T-AR^−/y) mice revealed incomplete germ cell development and lowered serum testosterone levels, which resulted in azoospermia and infertility. However, the consequences of AR loss in particular types of testicular cells remain unclear. Using a Cre-loxP conditional knockout strategy, we generated a tissue-selective knockout mouse with the AR gene deleted in testis peritubular myoid cells (PM-AR^−/y). Phenotype analyses showed that PM-AR^−/ymice were indistinguishable from WT AR (AR^+/y) mice with the exception of smaller testes size. PM-AR^−/ymice have serum testosterone concentrations comparable with AR^+/ymice. PM-AR^−/ymice have oligozoospermia in the epididymis; however, fertility was normal. Although normal germ cell distribution ratio was found, total germ cell number decreased in PM-AR^−/ymice. Further mechanistic studies demonstrated that PM-AR^−/ymice have defects in the expression of Sertoli cells' functional marker genes such as tranferrin, epidermal fatty acid-binding protein, androgen-binding protein, and other junction genes including occludin, testin, nectin, zyxin, vinculin, lamininγ3, gelsolin, connection43, and N-cadherin. Furthermore, there were defects in peritubular myoid cell contractility-related genes such as endothelin-1, endothelin receptor A and B, adrenomedullin, adrenomedullin receptor, and vasopressin receptor 1a. Together, our PM-AR^−/ymice providein vivoevidence for the requirement of functional AR in peritubular myoid cells to maintain normal Sertoli cells function and peritubular myoid cell contractility, thus ensuring normal spermatogenesis and sperm output.

20-Hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE) is a cytochrome P450 (CYP)–derived omega-hydroxylation metabolite of arachidonic acid. 20-HETE has been shown to play a complex role in blood pressure regulation. In the kidney tubules, 20-HETE inhibits sodium reabsorption and promotes natriuresis, thus, contributing to antihypertensive mechanisms. In contrast, in the microvasculature, 20-HETE has been shown to play a pressor role by sensitizing smooth muscle cells to constrictor stimuli and increasing myogenic tone, and by acting on the endothelium to further promote endothelial dysfunction and endothelial activation. In addition, 20-HETE induces endothelial angiotensin-converting enzyme, thus, setting forth a potential feed forward prohypertensive mechanism by stimulating the renin–angiotensin–aldosterone system. With the advancement of gene sequencing technology, numerous polymorphisms in the regulatory coding and noncoding regions of 20-HETE–producing enzymes, CYP4A11 and CYP4F2, have been associated with hypertension. This in-depth review article discusses the biosynthesis and function of 20-HETE in the cardiovascular system, the pharmacological agents that affect 20-HETE action, and polymorphisms of CYP enzymes that produce 20-HETE and are associated with systemic hypertension in humans.