Our long term objectives are to provide new insight into the cellular signaling pathways that underlie the regulation of peripheral vascular resistance. The interaction between skeletal muscle contractions and sympathetic nerve activity (SNA) determines muscle blood flow and arterial pressure during exercise through governing the diameter of resistance vessels. The resistance network is comprised of arterioles embedded within the muscle and their feed arteries (FA) located extemal to the tissue. As motor unit recruitment and contractile activity increase, vasodilation is initiated on arterioles and """"""""ascends"""""""" into FA via cell-to-cell conduction of a signal (hyperpolarization) along the endothelium that relaxes surrounding smooth muscle cells. Resistance vessels are invested with sympathetic nerves; thus, arterioles and FA constrict progressively as SNA increases. With SNA during exercise, dilation prevails in downstream arterioles while constriction prevails in upstream FA, which thereby restricts muscle blood flow. Our working hypothesis is that ascending (conducted) vasodilation is modulated by SNA to govem muscle blood flow while maintaining arterial pressure.
Our Specific Aims are to: (1) Determine the signaling pathway(s) that initiate(s) ascending vasodUation; (2) Determine which ion channels underlie the initiation and the conduction of vasodUation; and (3) Determine how SNA modulates conducted vasodilation. Using the retractor muscle preparation in anesthetized hamsters, muscle fibers are stimulated to contract and vasomotor responses are observed using video microscopy. Individual FA are isolated and pressurized to record vasomotor and electrophysiological responses during conducted vasodilation and SNA. Underlying signaling pathways are investigated using specific pharmacological interventions, intracellular recording, and selective disruption of endothelium or smooth muscle function. Findings from these experiments will provide new, mechanistic insight into vascular determinants of physical performance and strengthen the foundation for understanding decrements in physical work capacity that occur with disease, inactivity, and aging. This insight will promote the development of novel strategies for the maintenance of an active lifestyle as well as rehabilitation and recovery from impaired physical work capacity. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056786-07
Application #
6900254
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Goldman, Stephen
Project Start
1996-07-01
Project End
2006-05-31
Budget Start
2005-08-01
Budget End
2006-05-31
Support Year
7
Fiscal Year
2005
Total Cost
$94,240
Indirect Cost
Name
John B. Pierce Laboratory, Inc.
Department
Type
DUNS #
010139210
City
New Haven
State
CT
Country
United States
Zip Code
06519
Segal, Steven S (2015) Integration and Modulation of Intercellular Signaling Underlying Blood Flow Control. J Vasc Res 52:136-57
Correa, Diego; Segal, Steven S (2012) Neurovascular proximity in the diaphragm muscle of adult mice. Microcirculation 19:306-15
Bagher, P; Segal, S S (2011) Regulation of blood flow in the microcirculation: role of conducted vasodilation. Acta Physiol (Oxf) 202:271-84
Bagher, Pooneh; Segal, Steven S (2011) The mouse cremaster muscle preparation for intravital imaging of the microcirculation. J Vis Exp :
Bagher, Pooneh; Duan, Dongsheng; Segal, Steven S (2011) Evidence for impaired neurovascular transmission in a murine model of Duchenne muscular dystrophy. J Appl Physiol 110:601-9
de With, M C J; de Vries, A M; Kroese, A B A et al. (2009) Vascular anatomy of the hamster retractor muscle with regard to its microvascular transfer. Eur Surg Res 42:97-105
Long, Jennifer B; Jay, Steven M; Segal, Steven S et al. (2009) VEGF-A and Semaphorin3A: modulators of vascular sympathetic innervation. Dev Biol 334:119-32
Bertram, James P; Williams, Cicely A; Robinson, Rebecca et al. (2009) Intravenous hemostat: nanotechnology to halt bleeding. Sci Transl Med 1:11ra22
Hakim, Chady H; Jackson, William F; Segal, Steven S (2008) Connexin isoform expression in smooth muscle cells and endothelial cells of hamster cheek pouch arterioles and retractor feed arteries. Microcirculation 15:503-14
Tallini, Yvonne N; Brekke, Johan Fredrik; Shui, Bo et al. (2007) Propagated endothelial Ca2+ waves and arteriolar dilation in vivo: measurements in Cx40BAC GCaMP2 transgenic mice. Circ Res 101:1300-9

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