Expression and regulation of endothelin-1 and its receptors in human penile smooth muscle cells

Abstract

We report for the first time that penile smooth muscle cells (SMC) not only respond to, but also synthesize, endothelin-1 (ET-1), one of the main regulators of SMC activity. Immunohistochemical studies indicated that, beside endothelial cells (EC), SMC of the human adult and fetal penis also express ET-1 and its converting enzyme, ECE-1. Accordingly, cultures of adult penile stromal cells express these genes. We also prepared and characterized penile SMC from human fetuses. These cells express SMC specific markers such as alpha smooth muscle actin and phosphodiesterase type 5A3 along with hallmarks of androgen-dependent cells (androgen receptor and 5alpha reductase type 2). Human fetal penile SMC (hfPSMC) are immunopositive for ET-1 and release ET-1. ET-1 expression in hfPSMC was strongly increased by several factors such as transforming growth factor-beta1 (TGF-beta1), interleukin-1alpha (IL-1alpha), ET-1 itself and prolonged (24 h) hypoxia. This latter condition not only affected ET-1 expression but also responsiveness. While at normal oxygen tension, hfPSMC responded to ET-1 with a decreased proliferation mediated by the endothelin-A receptors and TGF-beta1; however, during hypoxia, ET-1 stimulated cell growth. Accordingly, prolonged hypoxia up-regulated endothelin-B receptor mRNA expression. In conclusion, our results indicate that in penile tissues SMC produce ET-1 and that such production is modulated by factors involved in penile physiology and tissue remodelling. In addition, the hfPSMC we have characterized might be a useful model for studying biochemical aspects of the human erectile process in vitro.

Androgen depletion in humans leads to cavernous tissue reorganization and upregulation of Sirt1–eNOS axis

“…Interestingly, a previous report showed increased circulating levels of ET1 in hypogonadic men, which were normalized with testosterone replacement (Kumanov et al 2007). ET1 is in fact considered the most potent stimulator of penile SM cell contractility (Filippi et al 2003;Granchi et al 2002;Mills et al 2001;Saenz de Tejada et al 1991). Mainly originated in EC, ET1 was also evidenced in SM cells of the human penis (Granchi et al 2002;Saenz de Tejada et al 1991;present investigation) and is thus involved in paracrine and autocrine effects (Granchi et al 2002).…”

Effect of sildenafil administration on penile hypoxia induced by cavernous neurotomy in the rat

“…2 Later on, it has been clarified that ET-1 and its related peptides are also synthesized and released by penile endothelial 3 and fibro-muscular cells. 4 In the penis, ET-1 is a profibrotic peptide and the most potent stimulator of cavernosal contractility, acting on receptors identified in different animal species, including humans. [3][4][5][6][7][8][9] In human penile cells, ET-1 expression is upregulated by several factors such as transforming growth factor-b1 (TGF-b1), interleukin-1a, ET-1 itself and by prolonged (24 h) hypoxia.…”

“…4 In the penis, ET-1 is a profibrotic peptide and the most potent stimulator of cavernosal contractility, acting on receptors identified in different animal species, including humans. [3][4][5][6][7][8][9] In human penile cells, ET-1 expression is upregulated by several factors such as transforming growth factor-b1 (TGF-b1), interleukin-1a, ET-1 itself and by prolonged (24 h) hypoxia. 4 Hypoxia is a normal, physiological event in the penis, which, in the flaccid state, resides at a very low oxygen tension (P O 2 ¼ 25-40 mm Hg).…”

The role of vacuum erection devices in penile rehabilitation after radical prostatectomy

“…26 This leads to increased synthesis of endothelin-1, which is a constrictor of penile smooth muscle and a profibrotic agent. 27 This fibrosis leads to decreased EF. [28][29][30] Low oxygen tension also decreases the level of prostaglandin-E1, which normally inhibits collagen formation by inhibiting transforming growth factor-b 1.…”