Relationships of maternal serum levels of vascular endothelial growth factor and tensile strength properties of the cervix in a rat model of chronic hypoxia.
OBJECTIVE
It has been shown that hypoxia leads to alterations in maternal serum levels of vascular endothelial growth factor (VEGF). In this study, we sought to test the hypothesis that chronic hypoxia increases maternal serum levels of VEGF, which in turn cause measurable changes in the viscoelastic properties of the rat uterine cervix.


METHODS
Timed-pregnant adult Sprague-Dawley rats were exposed to hypoxia beginning on day 17 of gestation (term = day 22). The following groups of animals were studied: (1) nonpregnant controls (NP, n = 6); (2) normoxia 21% fraction of inspired oxygen (FiO2) (NMX, n = 6); and (3) severe hypoxia 10% FiO2 (HPX; n = 5). A hypoxic chamber was used to assure consistent hypoxic environment. Animals were killed on day 21 of gestation (before labor). Maternal blood was collected immediately following anesthesia and prior to euthanasia. Free serum levels of VEGF were measured by highly specific immunoassays. Tensile strength properties of the cervix were assessed using a stretching regimen designed to mimic labor. Physical parameters measured were: indicators of viscoelasticity (slope; measure of stiffness), plasticity (yield point [YP]; moment the tissue changes its properties from elastic to plastic), strength (break point [BP]; moment of tissue disruption), and displacement at YP (marks the duration of the viscoelastic phase of the stretching) and BP (a measure of the strength of the material). Data were normalized to the dry weight of the cervix.


RESULTS
Hypoxia is associated with increased serum levels of VEGF compared to NP or NMX groups (P = .001). Cervical stiffness was lower in NMX, compared with NP animals (P = .004), and was not significantly influenced by hypoxia (P > .05). Overall there was a significant inverse correlation between slope and maternal serum levels of VEGF (r = -0.85, P < .001). The force required to reach YP was significantly higher for the NP, compared with NMX and HPX groups (P = .004). Hypoxia did not alter the force required to reach the YP (NMX vs HPX, P > .05). Conversely, hypoxia significantly decreased the displacement at YP, indicating a shortening of the elastic phase (NMX vs HPX, P = .021). There was a significant inverse correlation between maternal serum levels of VEGF and the displacement at YP (r = -0.68, P = .002). In vivo, hypoxia decreased the force required to reached the BP (NMX vs HPX, P = .025), but there was no correlation between the levels of maternal serum VEGF and this indicator (r = -0.35, P = .170).


CONCLUSIONS
Chronic hypoxia induces measurable changes in maternal serum levels of VEGF and tensile properties of the rat cervix, specifically a shortening of the elastic phase. Hypoxia decreases the cervical strength to stretch and predisposes to rupture, but this effect seems to be unrelated to maternal serum levels of VEGF.
Sfakianaki
Anna K
AK
Department of Obstetrics, Gynecology, and Reproductive Science, Yale University School of Medicine, New Haven, CT 06520, USA.
Buhimschi
Irina A
IA
Ravishankar
Viswanathan
V
Bahtiyar
Mert Ozan
MO
Dulay
Antonette T
AT
Buhimschi
Catalin S
CS
D000818:Animals; D002584:Cervix Uteri / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005311:Fetal Hypoxia / Q000097:blood* / Q000503:physiopathology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013718:Tensile Strength; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
D042461:Vascular Endothelial Growth Factor A