Prolactin in eyes of patients with retinopathy of prematurity: implications for vascular regression.
OBJECTIVE
Disruption of the anti-angiogenic environment of the retina leads to neovascular eye diseases, including retinopathy of prematurity (ROP). Prolactin (PRL), the hormone originally associated with milk secretion, is proteolytically processed to 16K-PRL, a fragment with potent antiangiogenic, proapoptotic effects. Whether 16K-PRL is produced in eyes of patients with ROP and promotes the regression of intraocular blood vessels associated with this disease was investigated.


METHODS
PRL was quantified in the aqueous humor, subretinal fluid, and serum from patients with stage 5 ROP and in patients with non-neovascular eye disorders. Intraocular expression of PRL was evaluated by RT-PCR, in situ hybridization, and Western blot analysis. AntiPRL antibodies were injected intravitreously in neonatal rats, and apoptosis of hyaloid vessels determined by TUNEL and ELISA.


RESULTS
PRL was elevated in ocular fluids and serum from ROP patients. There was no correlation between PRL in ocular fluids and its level in serum, whereas PRL in aqueous humor and subretinal fluid were significantly correlated. PRL mRNA was expressed in blood vessels and leukocytes within retrolental fibrovascular membranes of ROP patients, and these membranes contained a 16 kDa immunoreactive PRL. The 16K-PRL isoform was more concentrated in subretinal fluid than in serum and was generated from PRL by subretinal fluid proteases. Intravitreous injection of neutralizing antiPRL antibodies inhibited the apoptosis of hyaloid vessels in neonatal rats.


CONCLUSIONS
16K-PRL derived from PRL internalized from the circulation or synthesized intraocularly can stimulate apoptosis-induced vascular regression and contribute to the development and progression of ROP.
Dueñas
Zulma
Z
Instituto de Neurobiología, Universidad Nacional Autónoma de México, Queretaro, Qro, Mexico.
Rivera
José C
JC
Quiróz-Mercado
Hugo
H
Aranda
Jorge
J
Macotela
Yazmín
Y
Montes de Oca
Pável
P
López-Barrera
Fernando
F
Nava
Gabriel
G
Guerrero
José L
JL
Suarez
Ana
A
De Regil
Mateo
M
Martínez de la Escalera
Gonzalo
G
Clapp
Carmen
C
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007223:Infant; D007231:Infant, Newborn; D007267:Injections; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011388:Prolactin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012178:Retinopathy of Prematurity / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014822:Vitreous Body / Q000098:blood supply
D000906:Antibodies; D020033:Protein Isoforms; D012333:RNA, Messenger; D011388:Prolactin