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Mechanisms of Vascular Toxicity from Inhaled Toxicants

Award Number: R01ES014639
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2008
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Mechanisms of Vascular Toxicity from Inhaled Toxicants - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$2,643 )
2026	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	16	12/3/2025	NON-COMPETING CONTINUATION	-$2,643
														Subtotal = -$2,643

Issue Date FY: 2023 ( Subtotal = $324,648 )
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	16	7/21/2023	NON-COMPETING CONTINUATION	$324,648
														Subtotal = $324,648

Issue Date FY: 2022 ( Subtotal = $324,648 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	15	8/10/2022	NON-COMPETING CONTINUATION	$324,648
														Subtotal = $324,648

Issue Date FY: 2021 ( Subtotal = $603,116 )
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	14	7/28/2021	SUPPLEMENT FOR EXPANSION	$278,468
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	14	7/27/2021	NON-COMPETING CONTINUATION	$324,648
														Subtotal = $603,116

Issue Date FY: 2020 ( Subtotal = $324,648 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	002	13	8/3/2020	NON-COMPETING CONTINUATION	$324,648
2020	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	12	3/13/2020	COMPETING CONTINUATION	$119,085
2020	2018	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	11	3/13/2020	NON-COMPETING CONTINUATION	-$119,085
														Subtotal = $324,648

Issue Date FY: 2019 ( Subtotal = $335,592 )
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	12	7/25/2019	COMPETING CONTINUATION	$335,592
2019	2018	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	11	7/16/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $335,592

Issue Date FY: 2018 ( Subtotal = $703,325 )
2018	2018	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	11	3/9/2018	NON-COMPETING CONTINUATION	$703,325
														Subtotal = $703,325

Issue Date FY: 2017 ( Subtotal = $703,049 )
2017	2017	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	10	3/21/2017	NON-COMPETING CONTINUATION	$703,049
														Subtotal = $703,049

Issue Date FY: 2016 ( Subtotal = $741,196 )
2016	2016	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	9	3/23/2016	NON-COMPETING CONTINUATION	$362,871
2016	2016	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	9	3/29/2016	SUPPLEMENT FOR EXPANSION	$378,325
														Subtotal = $741,196

Issue Date FY: 2015 ( Subtotal = $362,313 )
2015	2015	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	8	3/31/2015	NON-COMPETING CONTINUATION	$362,313
														Subtotal = $362,313

Issue Date FY: 2014 ( Subtotal = $366,857 )
2014	2014	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	7	6/2/2014	COMPETING CONTINUATION	$366,857
														Subtotal = $366,857

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	6	9/24/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $329,277 )
2012	2012	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	6	2/29/2012	NON-COMPETING CONTINUATION	$329,277
														Subtotal = $329,277

Issue Date FY: 2011 ( Subtotal = $329,033 )
2011	2011	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	5	6/9/2011	NON-COMPETING CONTINUATION	$29,912
2011	2011	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	5	4/7/2011	NON-COMPETING CONTINUATION	$299,121
														Subtotal = $329,033

Issue Date FY: 2010 ( Subtotal = $377,864 )
2010	2010	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	005	4	2/26/2010	NON-COMPETING CONTINUATION	$331,739
2010	2009	LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE	POST OFFICE BOX 5890	ALBUQUERQUE	NM	87185	BERNALILLO	USA	Environmental Health	000	2	11/6/2009	NON-COMPETING CONTINUATION	$46,125
2010	2009	LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE	POST OFFICE BOX 5890	ALBUQUERQUE	NM	87185	BERNALILLO	USA	Environmental Health	001	2	11/6/2009	NON-COMPETING CONTINUATION	-$206,731
2010	2009	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	004	3	12/11/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$206,731
2010	2009	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	003	3	12/7/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$206,731
2010	2009	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	002	3	11/6/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$206,731
														Subtotal = $377,864

Issue Date FY: 2009 ( Subtotal = $461,250 )
2009	2009	LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE	POST OFFICE BOX 5890	ALBUQUERQUE	NM	87185	BERNALILLO	USA	Environmental Health	001	2	3/23/2009	NON-COMPETING CONTINUATION	$46,125
2009	2009	LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE	POST OFFICE BOX 5890	ALBUQUERQUE	NM	87185	BERNALILLO	USA	Environmental Health	000	2	2/19/2009	NON-COMPETING CONTINUATION	$415,125
														Subtotal = $461,250

Issue Date FY: 2008 ( Subtotal = $461,250 )
2008	2008	LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE	POST OFFICE BOX 5890	ALBUQUERQUE	NM	87185	BERNALILLO	USA	Environmental Health	000	1	5/3/2008	NEW	$461,250
														Subtotal = $461,250

Grand Total All Awards = $6,745,423

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Mechanisms of Vascular Toxicity from Inhaled Toxicants

Award Number: R01ES014639

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2008

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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