Skip Navigation

MECHANISMS OF VASCULAR TOXICITY FROM INHALED TOXICANTS

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES014639&format=word)
Principal Investigator: Campen, Matthew J
Institute Receiving Award University Of New Mexico Health Scis Ctr
Location Albuquerque, NM
Grant Number R01ES014639
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 May 2008 to 31 Jul 2024
DESCRIPTION (provided by applicant): Air pollution exposure has a well-appreciated negative impact on vascular health. Over the past decade, several epidemiological reports have highlighted associations between particulate matter (PM) and ozone (O3) exposures and pregnancy-related events, including preeclampsia, peripartum cardiomyopathy, and adverse birth outcomes. In the past funding cycle, we have greatly expanded our understanding of the crucial pathways that are essential to systemic vascular responses to inhaled toxicants. Both particulate matter (PM) and gaseous pollutants have the capacity to induce proteolytic activity in the lung, leading to the shedding of protein fragments that are bioactive and promote endothelial inflammatory, antiangiogenic, and vasoconstrictive responses. We propose to use this knowledge to study the cardiovascular impacts of inhaled pollutants on maternal physiology during and after pregnancy, periods of vulnerability due to dynamic metabolic demands, cardiovascular remodeling, and angiogenesis. Our discoveries of vasoactive, endogenous protein fragments arising from exposure to inhaled pollutants raises questions for how such mechanisms may impact the highly dynamic cardiovascular system during and after pregnancy. We hypothesize that specific peptide motifs, shed from the lung in response to air pollutant exposure, can drive uterine arterial constriction and reduce placental angiogenesis during pregnancy, promoting the pathological feedback mechanisms that further predispose dams to cardiomyopathic remodeling postpartum. We propose to first characterize the impact that pulmonary peptidase-derived circulating factors arising from inhaled pollutants exert on uterine artery and placental endothelial function. We anticipate that peptide fragments shed from the lung after exposure to ozone O3 or ambient PM can negatively impact uterine artery tone during pregnancy and also impair placental vasculogenesis, leading to pathological placental insufficiency. Further, we will assess the role of pulmonary proteinases in creating the serum bioactive components by pharmacological inhibition of matrix metalloproteinase activity. Second, we will assess how early gestational exposure to pollutants (O3, PM) can perturb hemodynamic and cardiac structural changes in normal and perturbed models of pregnancy. We posit that pollutant-induced generation of constrictive factors, along with the placental antiangiogenic response, will increase uterine artery resistance and maternal systemic arterial blood pressure. Third, we will examine the pollutant-induced perturbation of normal cardiac hypertrophy pathways during pregnancy and involution pathways postpartum. We hypothesize that pollutant exposure during pregnancy will promote maladaptive hypertrophy through suppression of stat3 signaling and also impair cardiac atrophy postpartum, which will lead to irreversible, functional deficits. Lastly, we will investigate proteomic changes in the amniotic fluid relative to O3 concentration and temporal exposure dynamics. The amniotic fluid has a complex origin and may reflect pathological changes to the placenta or fetus, but it may also influence fetal development. These studies are designed to address a specific and important period of vulnerability that has been largely unstudied from the perspective of adverse environemental impacts on the mother.
Science Code(s)/Area of Science(s) Primary: 41 - Cardiovascular System
Secondary: 01 - Basic Cellular or Molecular processes
Publications See publications associated with this Grant.
Program Officer Thaddeus Schug
Back
to Top