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New Signaling Networks in Vascular Smooth Muscle

Award Number: R01HL147555
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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New Signaling Networks in Vascular Smooth Muscle - Abstract: This proposal focuses on our discovery of new signaling pathways mediated by the p90 ribosomal S6 kinase (RSK2) that regulate vascular smooth muscle (VSM) mediated vascular resistance, myogenic tone and blood flow with the rational that outcomes have potential to deliver new therapeutic targets. The myogenic response of small resistance arteries is critical for protection of downstream arterioles and capillaries against barotrauma due to excessive changes in intravascular pressure. Our understanding of the signaling pathways that control myogenic and agonist-mediated vasoconstriction, vascular resistance and blood pressure homeostasis are incomplete and this proposal addresses this gap in our knowledge base. Our overall objective is to determine the contribution of RSK2 to vascular physiology and pathophysiology from a mechanistic and functional perspective. Our central hypothesis is that RSK2 kinase mediates a novel network of pathways that result in regulation of VSM contraction in response to myogenic pressure and to agonists. This hypothesis is based on preliminary data identifying three RSK2 targets in resistance arteries which potentiate the contractile state: (1) RLC20, leading to direct augmentation of the canonical activation of myosin cross-bridge function; (2) NHE-1 Na+/H+ exchanger, the phosphorylation of which contributes to an increase in pHi associated with an increase in cytosolic [Ca2+], thereby potentiating the MLCK-mediated pathway; and (3) two RhoA-specific nucleotide exchange factors, with potential regulatory impact on the RhoA-mediated pathway. Our preliminary data also suggest that RSK2 signaling contributes ~20% of maximal myogenic force and that arteries from a Rsk2-/- mouse or treated with RSK inhibitors are more dilated, have reduced myogenic tone and RLC20 phosphorylation and that Rsk2-/- mice have lower blood pressure compared to wild-type mice. We hypothesize that this non-canonical RSK2 pathway augments and cross talks with the canonical Ca2+/MLCK and RhoA/ROCK Ca2+-sensitization pathways to regulate vasoconstriction and basal BP. The following aims test our hypotheses: Aim 1: To determine how RSK2 contributes to VSM contraction in response to perfusion pressure and agonists, with a focus on select phosphorylation targets, i.e. RLC20, NHE-1 and RhoGEFs. Aim 2: To assess the contribution of RSK2 to blood pressure homeostasis. Outcomes are expected to establish and add a new RSK2 mediated signaling network to the canonical MLCK and RhoA/ROCK signaling pathways regulating VSM tone and vasoconstriction and to provide possible new therapeutic targets for contractile pathologies of the vessel wall.


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: 2025 ( Subtotal = $0 )
2025	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	11/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $171,494 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	2/9/2024	SUPPLEMENT FOR EXPANSION	$171,494
														Subtotal = $171,494

Issue Date FY: 2023 ( Subtotal = $1,004,155 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	002	4	2/17/2023	NON-COMPETING CONTINUATION	$214,449
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	12/1/2022	NON-COMPETING CONTINUATION	$647,164
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	4	12/2/2022	SUPPLEMENT FOR EXPANSION	$142,542
														Subtotal = $1,004,155

Issue Date FY: 2022 ( Subtotal = $861,613 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	3	11/30/2021	SUPPLEMENT FOR EXPANSION	$142,542
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	3	11/26/2021	NON-COMPETING CONTINUATION	$647,164
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	002	3	6/20/2022	NON-COMPETING CONTINUATION	$71,907
														Subtotal = $861,613

Issue Date FY: 2021 ( Subtotal = $861,613 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	2	5/24/2021	NON-COMPETING CONTINUATION	$86,162
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	2	12/24/2020	NON-COMPETING CONTINUATION	$775,451
														Subtotal = $861,613

Issue Date FY: 2020 ( Subtotal = $737,979 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	1	9/23/2020	SUPPLEMENT FOR EXPANSION	$47,749
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	1	1/14/2020	NEW	$690,230
														Subtotal = $737,979

Grand Total All Awards = $3,636,854

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New Signaling Networks in Vascular Smooth Muscle

Award Number: R01HL147555

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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