Osol Lab Research
Our research is focused on the process of uterine artery remodeling during normal vs. hypertensive pregnancy. Unlike most blood vessels in the body that change little once one becomes an adult, the vasculature of the uterus undergoes remarkable expansive growth during gestation through a widening and lengthening of both arteries and veins. This facilitates the >10x increase in uterine blood flow and occurs in conjunction with the development of the placenta, an entirely new circulation.
From a clinical standpoint, insufficient remodeling or excessive constriction lead to placental underperfusion, the initial "lesion" that eventually leads to the development of serious gestational diseases like preeclampsia and intrauterine growth restriction (IUGR). Therefore, understanding the patterns, pathways and molecular signals involved in gestational uterine vascular remodeling is important from both a fundamental physiological and a clinical standpoint.
Using rats as the animal of choice, we also treat pregnant rats with a compound (L-NAME) that inhibits the production of nitric oxide, a vasodilator molecule that plays a central role in vascular function. This results in systemic hypertension and a preeclampsia-like condition. By comparing arterial and venous remodeling in control vs. L-NAME treated rats, we are then able to investigate the effects of NO inhibition/hypertension on the remodeling process.
Ultimately, blood flow depends on the caliber of the vessel, but also on its extent of constriction, or tone, i.e. "functional remodeling". By measuring changes in vascular structure and contractility, we able to create a reasonably complete picture of vascular function, and thereby evaluate how these processes interact to regulate uteroplacental blood flow.
Pregnancy and hypertension each induce selective (and sometimes opposing) changes in vessel structure (caliber and length) and function (tone and reactivity). Understanding the underlying mechanisms responsible for these changes in both normal and preeclamptic (hypertensive) pregnancy is the main focus of our research, which has been supported by the NIH for >25 years
Active Grant Support
Title: VEGFR-1 in the Uterine Circulation
Sponsor: National Institutes of Health, 2008-2012
Title: Induction of uterine vascular remodeling by myometrial stretch, R21
Sponsor: National Institutes of Health, 2011-2013
The experimental techniques that we routinely utilize include
- Surgery for implantation of osmotic pumps for drug delivery, manipulating (e.g. stretching) the uterus, or restricting pregnancy to one uterine horn.
- Small artery pressure myography, which involves isolating and cannulating resistance arteries from the uterus and elsewhere (e.g. gut) and studying their behavior in vitro, under pressurized conditions using video-electronic instrumentation.
- Pharmacologic interventions (in vivo and in vitro) to inhibit or stimulate particular cellular signaling pathways and observe their effect on vascular structure and function.
- Transmission and scanning electron microscopy and light microscopy to evaluate changes in cellular structure and ultrastructure.
- Molecular techniques such as RT-PCR and Western blotting to quantify changes in enzyme levels and activity (e.g. eNOS, PKG).
- Non-invasive blood pressure measurement using tail cuff oscillometry to determine the extent of hypertension, and evaluate the efficacy of antihypertensive treatment.