The long-term goal of this project is to define the cellular and molecular mechanisms that govern the integration and coordination of blood flow control. Electrical and vasomotor responses are conducted rapidly along arterioles and feed arteries to coordinate vasodilation and vasoconstriction in resistance networks. The working hypothesis is that conduction reflects the transmission of hyperpolarization (dilation) or depolarization (constriction) through gap junctions between endothelial cells (EC) and between smooth muscle cells (SMC) that comprise the vessel wall. The role of EC and SMC layers in conduction is unclear, as is the nature of coupling between respective layers. Further, conduction varies between microvessels of the epithelial hamster cheek pouch and its contiguous retractor (skeletal) muscle. The basis of these regional differences may be associated with corresponding differences in sympathetic innervation and/or gap junction expression within and between cell layers. Arterioles and feed arteries from cheek pouch and retractor will be studied in vivo and in vitro.
The specific aims are to determine: 1) the role of EC and SMC as conduction pathways; 2) the nature of coupling between EC and SMC layers; and 3) the influence of sympathetic innervation and gap junction expression on conducted vasomotor responses. Micropipettes deliver stimuli that act selectively on SMC or on EC, and intracellular recording with dye labeling resolves SMC and EC specific signaling events. Selective disruption of EC or SMC signaling is achieved through light dye damage and pharmacological intervention. The results will define the roles of EC and SMC layers as signaling pathways, define the nature (chemical and/or electrical) of communication between EC and SMC layers, and will link the determinants of conduction with regional differences in innervation and gap junction expression. These findings will provide insight into how the control of microvascular resistance may vary between tissues that differ in structure and function. In addition, distinguishing the roles of SMC and EC in the initiation and conduction of vasomotor responses in vessels that control blood flow to epithelium and skeletal muscle will contribute to the understanding of how tissue perfusion is compromised in conditions such as atherosclerosis, diabetes, hypertension, and ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL041026-12
Application #
6526704
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Goldman, Stephen
Project Start
1988-07-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
12
Fiscal Year
2002
Total Cost
$276,463
Indirect Cost
Name
John B. Pierce Laboratory, Inc.
Department
Type
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06519
Kapela, Adam; Behringer, Erik J; Segal, Steven S et al. (2018) Biophysical properties of microvascular endothelium: Requirements for initiating and conducting electrical signals. Microcirculation 25:
Behringer, Erik J; Segal, Steven S (2012) Tuning electrical conduction along endothelial tubes of resistance arteries through Ca(2+)-activated K(+) channels. Circ Res 110:1311-21
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
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
Uhrenholt, Torben R; Domeier, Timothy L; Segal, Steven S (2007) Propagation of calcium waves along endothelium of hamster feed arteries. Am J Physiol Heart Circ Physiol 292:H1634-40
Domeier, Timothy L; Segal, Steven S (2007) Electromechanical and pharmacomechanical signalling pathways for conducted vasodilatation along endothelium of hamster feed arteries. J Physiol 579:175-86
Brekke, Johan Fredrik; Jackson, William F; Segal, Steven S (2006) Arteriolar smooth muscle Ca2+ dynamics during blood flow control in hamster cheek pouch. J Appl Physiol 101:307-15
Segal, Steven S (2005) Regulation of blood flow in the microcirculation. Microcirculation 12:33-45
Haug, Sara J; Segal, Steven S (2005) Sympathetic neural inhibition of conducted vasodilatation along hamster feed arteries: complementary effects of alpha1- and alpha2-adrenoreceptor activation. J Physiol 563:541-55

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