Relaxin Signaling


Pathway Description

Relaxin is a polypeptide hormone best known for its connective tissue remodeling effects on the female reproductive system. It is secreted by the corpus luteum into the circulation during the menstrual cycle and throughout pregnancy. It has diverse actions in the reproductive tract and other tissues during pregnancy. These actions include promotion of growth and dilation of the cervix, growth and quiescence of the uterus, growth and development of the mammary gland and nipples, expansion of the skin, reduction in the amplitude of spontaneous contractions of the intestine, and regulation of cardiovascular function. Its primary function in pregnancy is in remodeling of the cervix and the interpubic ligament in preparation for parturition.Relaxin belongs to the insulin-like growth factor (IGF) family of growth factors. It acts through 2 orphan heterotrimeric GPCRs: LGR7 and LGR8. It has pleiotropic signaling effects in several cells activating ERKs, cAMP, PI3K, and PKC-ζ.

Ligation of Relaxin LGR7 or LGR8 leads to stimulation of AC and an increase in cAMP. Binding of relaxin to its receptor also activates a tyrosine kinase pathway that inhibits phosphodiesterases (PDE), enzymes responsib for degradation of cAMP. cAMP in turn activates PKA, which leads to activation of transcription factors such as CREB and NF-κB. PKA phosphorylates and inactivates IκB-α, the inhibitor subunit of the transcription factor NF-κB, thus allowing NF-κB to translocate into the nucleus, and to bind to the NOS promoter. Relaxin can act on several of its targets by increasing the expression and/or activity of NOS isoenzymes, thereby promoting the generation of nitric oxide (NO). NOS3 can be activated by direct stimulation of the βγ subunits of the G proteins. This is accomplished by means of stimulation of PI3K, followed by Akt activation, which in turn activates NOS3 by phosphorylation.

Relaxin elicits a powerful vasodilatory response in several target organs. This response is mediated by the stimulation of intrinsic NO generation. The uterus is the site of NO production and expresses NOS, which are upregulated during pregnancy by relaxin. NO induces uterine quiescence, which is deemed necessary for the maintenance of pregnancy. Relaxin increases intracellular cGMP levels in a concentration-dependent manner. This effect of relaxin is likely a consequence of the stimulation of NO production by this hormone. In fact, NO binds to the heme iron of soluble guanylate cyclase and thereby activates the synthesis of cGMP. In turn, increased production of cGMP plays an important role in vasorelaxation. Moreover, relaxin induces changes in cell shape and the actin cytoskeleton that are consistent with cell relaxation. Relaxin specifically induces the expression of angiogenic agent, VEGF in the endometrium and, hence, is responsible for the formation of new blood vessels that are essential for embryonic growth and development.

In addition to its effects on female reproductive tissues, relaxin is also produced in the male prostate, released into seminal fluid, and may enhance sperm motility. It also has a role in regulating pituitary hormone release, renal vasculature, and lung and skin remodeling as well as in heart failure, angiogenesis, and tumor formation. It also stimulates an increase in heart rate and coronary blood flow and increases both glomerular filtration rate and renal plasma flow. In brain, relaxin binds to receptors in the circumventricular organs to affect blood pressure and drinking. Relaxin elicits remarkable pleiotropic characteristics with potential physiological and clinical significance that include decreasing fibrosis, inhibition of histamine release, stimulation of angiogenesis, modulation of blood pressure, enhancement of neuropeptide release, regulation of heart rate, and association with congestive heart failure.