Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat

Abstract

Endometriosis is a poorly understood, estradiol-dependent condition associated with severe pelvic pains and defined by vascularized endometrial growths outside the uterus. Endometriosis is produced in cycling rats by autotransplanting pieces of uterus onto abdominal arteries where they develop into cysts. The surgery induces vaginal and abdominal muscle hyperalgesia, whose severity is greatest in proestrus and nearly absent in estrus. The cysts contain growth factors and cytokines and develop their own sympathetic and sensory C-and A␦-fiber innervation. Here, we used quantitative immunostaining and protein array analyses to test the hypothesis that the innervation and growth factor/cytokine content of the cysts, but not uterine horn, contribute to proestrous-to-estrous changes in hyperalgesic severity. If so, these characteristics in the cysts, but not the uterine horn, should change with estrous stage. In cysts, the density of sympathetic (but not sensory) neurites and amounts of NGF and VEGF proteins (but not cytokines IL-1, IL-6, IL-10, or TNF-␣) were greater in proestrus than estrus. These changes were accompanied by vascular changes. Both sympathetic and sensory fibers in both stages colabeled with TrkA, indicating that changes in NGF could act on both afferent and efferent fibers. In contrast with the cysts, no changes occurred in the uterine horn between proestrus and estrus. Together, these results suggest that coordinated proestrous-to-estrous changes in innervation and vascularization of the cysts contribute to similar changes in hyperalgesic severity. The findings also encourage consideration of endometriosis as a neurovascular condition.

Proangiogenic features in chronic pelvic pain caused by adenomyosis

“…The data obtained on the excessive expression of VEGF in adenomiose coincide with the results of the study [14] where it was shown that it has a diffuse character, both in the myometrium and ectopic endometrium, the relative area of expression of VEGF in adenomyosis is of 11.51 ± 1.33%, which is 57% higher than in the control group, where the rate was equal to 7.32 ± 1.03%. But the obtained [14] data did not concern patients with the painful form of adenomyosis.…”

Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis

“…Notably, NGF can increase the number of sensory neurons and is selectively trophic for the small fiber sensory neurons and sympathetic ganglion neurons, which participate in mediating pain sensation [10,33]. Based on these observations, the nerve fibers present in endometriotic lesions are most likely a mixture of sensory Ad, sensory C, cholinergic and adrenergic nerve fibers, as determined by the staining pattern sion was up-regulated in artificially induced endometriotic lesions [22,23]. We have shown for the first time that these lesions exhibit an abundance of NGF transcripts, which explains the elevated levels of its protein.…”

“…Recently, it has been reported that nerve fiber density and expression levels of NGF in deep infiltrating endometriosis are much higher than in superficial peritoneal endometriotic lesions [31]. Also, in rodent models of endometriosis, NGF expression is up-regulated with resulting development of numerous nerve fibers within the endometriotic lesions [22,23,32]. Notably, NGF can increase the number of sensory neurons and is selectively trophic for the small fiber sensory neurons and sympathetic ganglion neurons, which participate in mediating pain sensation [10,33].…”

Endometriosis-associated pain syndrome: a nurse-led approach

“…Zhang et al 20 suggest that endometriosis is a neurovascular condition much like headache, a concept that was also suggested clinically. 21 Certainly here, as in other chronic pain type mechanisms, a combined complex circuitry of peripheral and central sensitisation mechanisms are in play.…”

“…There is also an implication of chemical changes, for example in the central neuromodulator N-Methyl-D-aspartate. 7 There is also evidence that painful endometriosis can be classified as a mixed inflammatory and neuropathic pain condition 25 or a neurovascular condition, 20 both of which open new avenues for pain relief.…”