Estrogen Elicits Dorsal Root Ganglion Axon Sprouting via a Renin-Angiotensin System

Abstract

Many painful conditions occur more frequently in women, and estrogen is a predisposing factor. Estrogen may contribute to some pain syndromes by enhancing axon outgrowth by sensory dorsal root ganglion (DRG) neurons. The objective of the present study was to define mechanisms by which estrogen elicits axon sprouting. The estrogen receptor-alpha agonist propyl pyrazole triol induced neurite outgrowth from cultured neonatal DRG neurons, whereas the estrogen receptor-beta agonist diarylpropionitrile was ineffective. 17beta-Estradiol (E2) elicited sprouting from peripherin-positive unmyelinated neurons, but not larger NF200-positive myelinated neurons. Microarray analysis showed that E2 up-regulates angiotensin II (ANGII) receptor type 2 (AT2) mRNA in vitro, and studies in adult rats confirmed increased DRG mRNA and protein in vivo. AT2 plays a central role in E2-induced axon sprouting because AT2 blockade by PD123,319 eliminated estrogen-mediated sprouting in vitro. We assessed whether AT2 may be responding to locally synthesized ANGII. DRG from adult rats expressed mRNA for renin, angiotensinogen, and angiotensin converting enzyme (ACE), and protein products were present and occasionally colocalized within neurons and other DRG cells. We determined if locally synthesized ANGII plays a role in estrogen-mediated sprouting by blocking its formation using the ACE inhibitor enalapril. ACE inhibition prevented estrogen-induced neuritogenesis. These findings support the hypothesis that estrogen promotes DRG nociceptor axon sprouting by up-regulating the AT2 receptor, and that locally synthesized ANGII can induce axon formation. Therefore, estrogen may contribute to some pain syndromes by enhancing the pro-neuritogenic effects of AT2 activation by ANGII.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Developmental Regulation. Human tissue expression of AT 2 receptor has been documented by immunocytochemistry, reverse transcriptase-polymerase chain reaction, and microarray analyses de Gasparo et al, 2000;Herradon et al, 2004;Kim et al, 2005b;Chakrabarty et al, 2008;Petracco et al, 2012). In most tissues, the AT 1 receptor and AT 2 receptor coexist.…”

Molecular mechanisms involved in the regulation of neuritogenesis by estradiol: Recent advances

“…However, it is important to consider that other endocrine, paracrine and autocrine factors may interact with the hormone to coordinate neuritogenesis. Thus, extracellular signals such as nitric oxide, apolipoprotein E and angiotensin II are involved in the neuritogenic actions of the hormone in some neuronal types [62][63][64]. Probably, future studies will clarify the interaction of estradiol with the signaling mechanisms of other major modulators of neuritogenesis under physiological and pathological conditions.…”

Estrogen Receptors: Their Actions and Functional Roles in Health and Disease

“…In the ovariectomized rat hot flush model both PPT and the ERβ-selective agonist, DPN, reversed the increase in tail skin temperature [409]. PPT but not DPN indirectly promoted sprouting of dorsal root ganglion nociceptors, suggesting that ERα may have implications for female pain syndromes [410]. E2 was shown to have an antidepressant effect in various strains of ovariectomized mice but lack of effect in ERβ deficient (BERKO) mice, suggesting a specific role of ERβ in mood and behaviour [411].…”

“…Ligands with ER subtype-selective affinity and biological activity have been reported [113,284,272,285,390,283,115,413,482,385,341,472,355,464,471,414,410,286,412,418,420,407,426,477]. A herbal extract with roughly similar affinity to both ERα and ERβ but with ERβ-selective transcriptional and biological activity has been described [439,446].…”