Faculty Collaboration Database

Identification of a putative microvascular oxygen sensor. Circ Res 1996 Jul;79(1):54-61

Date

07/01/1996

Pubmed ID

8925569

DOI

10.1161/01.res.79.1.54

Scopus ID

2-s2.0-0029947046 (requires institutional sign-in at Scopus site)   178 Citations

Abstract

The vascular response to changes in oxygen levels in the blood and tissue is a highly adaptive physiological response that functions to match tissue oxygen supply to metabolic demand. Defining the cellular mechanisms that can sense physiologically relevant changes in PO2 and adjust vascular diameter are vital to our understanding of this process. A cytochrome P450 (P450) enzyme of the 4A family of omega-hydroxylases was localized in renal microvessels, renal cortex, and a striated muscle microvascular bed (cremaster) of the rat. In the presence of molecular oxygen, this P450 enzyme catalyzes formation of 20-HETE from arachidonic acid (AA). Prior studies have shown that 20-HETE potently contracts renal and cerebral arteries and arterioles. The present study demonstrates that 20-HETE constricts striated muscle arterioles as well. In both intact renal microvessels and enriched renal cortical microsomal enzyme preparations, the formation of 20-HETE was linearly dependent on PO2 between 20 and 140 mm Hg. Homogenates of cremaster tissue produced 20-oxygen HETE when incubated with AA. They also expressed message for P450 4A enzyme, as determined by Southern and Western blots. Administration of 17-octadecynoic acid (17-ODYA), which is a P450 4A inhibitor, attenuated the constriction of third-order cremasteric arterioles in response to elevation of superfusion solution PO2 from approximately equal to 3 to 5 mm Hg to approximately equal to 35 mm Hg. 17-ODYA had no effect on basal vascular tone or response of cremaster arterioles to vasoactive compounds. These results demonstrate the existence of P450 omega-hydroxylase activity and 20-HETE formation in the vasculature and parenchyma of at least two microvascular beds. Our data suggest that a P450 enzyme of the 4A family has the potential to function as an oxygen sensor in mammalian microcirculatory beds and to regulate arteriolar caliber by generating 20-HETE in an oxygen-dependent manner.

Author List

Harder DR, Narayanan J, Birks EK, Liard JF, Imig JD, Lombard JH, Lange AR, Roman RJ

Authors

David Harder PhD, MS Emeritus Professor in the Physiology department at Medical College of Wisconsin
Julian Lombard PhD, MS Emeritus Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
Cytochrome P-450 CYP4A
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System
Fatty Acids, Unsaturated
Hydroxyeicosatetraenoic Acids
Male
Microcirculation
Mixed Function Oxygenases
Molecular Probes
Molecular Sequence Data
Muscle, Skeletal
Oxygen
Rats
Rats, Sprague-Dawley
Renal Circulation
Vasoconstriction