My long term career goal is to clarify how the microvascular smooth muscle cell integrates the large array of neural, humoral and local physio-chemical signals that it receives into an appropriate contractile response. My immediate research goal is to expand my current focus on the role of cell membrane receptors to include 2nd messenger systems and intracellular ion activity in the regulation of smooth muscle at the cellular, isolated microvessel and in situ microvascular levels. This requires, in addition to my current applications of receptor pharmacology, in situ microcirculatory and systemic hemodynamic analyses, the new techniques of receptor autoradiography and immuno-cytochemistry and in situ ion probe microfluorimetry. The objective of this proposal is to focus on alpha-adrenoceptor subtypes on microvascular smooth muscle type may be differentially governed by a heterogeneous distribution of alpha 1 and alpha 2 adrenoceptors (arterioles- alpha1/alpha2, precapillary spincters- alpha2, muscular venules-alpha2/alpha1), and that metabolic, myogenic, physiochemical (eg, temperature, pH), hormonal (eg, ANF) and neural (synaptic vs. extrasynaptic) signals interact selectively with alpha1 or alpha2 responses. Thus 3 novel hypotheses will be distinct microvascular segments. (2) alpha subtypes contraction is modulated differently by intrinsic and extrinsic controllers. (3) Heterogeneity of receptor distribution and sensitivity to smooth muscle controllers confers distinct regulatory features on microvascular segments: ie, alpha receptor subtypes serve unique physiological functions. Intravital microscopy of skeletal muscle and intestinal microvasculature will be used to characterize alpha adrenoceptors (K/M, pA2, receptor reserve) Aim I); examine interaction among intrinsic and extrinsic controllers on alpha subtype contraction (Aim II); determine the functional and anatomic (autoradiography) distribution of pre- and postjunctional alpha receptors across the microvasculature (Aim III); and examine whether alpha subtypes serve distinct physiological roles. The result will clarify basic mechanisms of microvascular regulation and may lead to new insights in the pathophysiology and treatment of peripheral vascular disorders.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Modified Research Career Development Award (K04)
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Experimental Cardiovascular Sciences Study Section (ECS)
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Leech, C J; Faber, J E (1996) Different alpha-adrenoceptor subtypes mediate constriction of arterioles and venules. Am J Physiol 270:H710-22
Tateishi, J; Faber, J E (1995) Inhibition of arteriole alpha 2- but not alpha 1-adrenoceptor constriction by acidosis and hypoxia in vitro. Am J Physiol 268:H2068-76
Tateishi, J; Faber, J E (1995) ATP-sensitive K+ channels mediate alpha 2D-adrenergic receptor contraction of arteriolar smooth muscle and reversal of contraction by hypoxia. Circ Res 76:53-63
Ikeoka, K; Faber, J E (1993) ANG II reverses selective inhibition of alpha 2-adrenoceptor sensitivity after in vitro isolation of arterioles. Am J Physiol 265:H1988-95
Ping, P; Faber, J E (1993) Characterization of alpha-adrenoceptor gene expression in arterial and venous smooth muscle. Am J Physiol 265:H1501-9
Magers, S; Faber, J E (1992) Real-time measurement of microvascular dimensions using digital cross-correlation image processing. J Vasc Res 29:241-7
Ikeoka, K; Nishigaki, K; Ohyanagi, M et al. (1992) In vitro analysis of alpha-adrenoceptor interactions with the myogenic response in resistance vessels. J Vasc Res 29:313-21
Ohyanagi, M; Nishigaki, K; Faber, J E (1992) Interaction between microvascular alpha 1- and alpha 2-adrenoceptors and endothelium-derived relaxing factor. Circ Res 71:188-200
Muldowney, S M; Faber, J E (1991) Preservation of venular but not arteriolar smooth muscle alpha-adrenoceptor sensitivity during reduced blood flow. Circ Res 69:1215-25
Ohyanagi, M; Faber, J E; Nishigaki, K (1991) Differential activation of alpha 1- and alpha 2-adrenoceptors on microvascular smooth muscle during sympathetic nerve stimulation. Circ Res 68:232-44

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