Vascular smooth muscle (VSM) cyclic guanosine 3',5'-moriophosphate (cGMP) serves as a criticalregulator of many cellular functions that contribute to vessel growth after injury. Nitric oxide (NO) andcarbon monoxide (CO) operate as soluble guanylate cyclase (sGC)-activating ligands for cGMP synthesis;however, limitations of NO and CO signaling warrant study into alternate, pathophysiologically relevantroutes for cGMP control. Provocative new findings challenge the traditional notion that cGMP exertsvascular protection through cGMP-dependent protein kinase type (cGKI) and suggest that cGMP mayoperate via cAMP/cAK to promote vascular protection. Current studies in our laboratory focus on novel NOindependentapproaches for cGMP control as significant basic science tools and as potential cardiovasculartherapeutics. Preliminary data support a role for vascular growth control by NO-independent cGMP andsuggest mechanistic involvement of matrix metalloproteinase (MMP)-2 and MMP-9. The long-term objectiveof this research project is to investigate strategies for cGMP control of VSM growth, and the centralhypothesis of this proposal is that NO-independent cGMP protects against vascular growth and that thisoccurs through cAK signals.
Two Specific Aims will be used to test this hypothesis:
Aim 1 will analyze the roles of NO-independent cGMP and cGMP-directed cGKI/cAK signaling inattenuating vascular remodeling in the rat balloon injury and mouse wire denudation injury models.
Aim 2 will examine matrix-based mechanisms including cell migration and MMP balance that underliecGMP-mediated growth control in rat and mouse primary VSM cells.Pharmacology, RNA interference, and viral gene delivery approaches will be used, and conditional VSMspecificcGKI-deficient models will allow direct comparison of cGKI versus cAK mechanisms. Results areanticipated to provide insight into and further evidence for NO-independent cGMP control of the injurygrowth response in VSM and shed light upon cGMP-directed MMPs in mediating these events.Injuries and diseases of the heart and blood vessels are wide-ranging and very serious public healthconcerns, and statistics show they are still the major cause of death in American populations. We believethat results from these studies will shed light on some novel and promising strategies that could be used tominimize the severity of blood vessel injury and disease and may offer beneficial prospects for further studyin basic science research and human-based clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL081720-03
Application #
7688384
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2008-09-24
Budget End
2009-04-30
Support Year
3
Fiscal Year
2008
Total Cost
$262,896
Indirect Cost
Name
East Carolina University
Department
Physiology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Holland, Nathan A; Francisco, Jake T; Johnson, Sean C et al. (2018) Cyclic Nucleotide-Directed Protein Kinases in Cardiovascular Inflammation and Growth. J Cardiovasc Dev Dis 5:
Tulis, David A (2017) Novel protein kinase targets in vascular smooth muscle therapeutics. Curr Opin Pharmacol 33:12-16
Holt, Andrew W; Howard, William E; Ables, Elizabeth T et al. (2017) Making the cut: Innovative methods for optimizing perfusion-based migration assays. Cytometry A 91:270-280
Holt, Andrew W; Martin, Danielle N; Shaver, Patti R et al. (2016) Soluble guanylyl cyclase-activated cyclic GMP-dependent protein kinase inhibits arterial smooth muscle cell migration independent of VASP-serine 239 phosphorylation. Cell Signal 28:1364-79
Stone, Joshua D; Holt, Andrew W; Vuncannon, Jackson R et al. (2015) AMP-activated protein kinase inhibits transforming growth factor-?-mediated vascular smooth muscle cell growth: implications for a Smad-3-dependent mechanism. Am J Physiol Heart Circ Physiol 309:H1251-9
Johnson, Tracy L; Tulis, David A; Keeler, Benjamin E et al. (2013) The dopamine D3 receptor knockout mouse mimics aging-related changes in autonomic function and cardiac fibrosis. PLoS One 8:e74116
Stone, Joshua D; Narine, Avinash; Shaver, Patti R et al. (2013) AMP-activated protein kinase inhibits vascular smooth muscle cell proliferation and migration and vascular remodeling following injury. Am J Physiol Heart Circ Physiol 304:H369-81
Holt, Andrew W; Tulis, David A (2013) Experimental Rat and Mouse Carotid Artery Surgery: Injury & Remodeling Studies. ISRN Minim Invasive Surg 2013:
Joshi, Chintamani N; Martin, Danielle N; Shaver, Patti et al. (2012) Control of vascular smooth muscle cell growth by connexin 43. Front Physiol 3:220
Stone, Joshua D; Narine, Avinash; Tulis, David A (2012) Inhibition of vascular smooth muscle growth via signaling crosstalk between AMP-activated protein kinase and cAMP-dependent protein kinase. Front Physiol 3:409

Showing the most recent 10 out of 24 publications