IDENTIFICATION OF A PUTATIVE MICROVASCULAR OXYGEN SENSOR

The vascular response to changes in oxygen levels in the blood and tis sue is a highly adaptive physiological response that functions to matc h tissue oxygen supply to metabolic demand. Defining the cellular mech anisms that can sense physiologically relevant changes in PO2 and adju st vascular diameter are vital to our understanding of this process. A cytochrome P450 (P450) enzyme of tile 4A family of omega-hydroxylases was localized in renal microvessels, renal cortex, and a striated mus cle microvascular bed (cremaster) of the rat. In the presence of molec ular oxygen, this P450 enzyme catalyzes formation of 20-HETE from arac hidonic acid (AA). Prior studies have shown that 20-HETE potently cont racts renal and cerebral arteries and arterioles. The present study de monstrates that 20-HETE constricts striated muscle arterioles as well. In both intact renal microvessels and enriched renal cortical microso mal enzyme preparations, the formation of 20-HETE was linearly depende nt on PO2 between 20 and 140 mm Hg. Homogenates of cremaster tissue pr oduced 20-oxygen HETE when incubated with AA. They also expressed mess age for P450 4A enzyme, as determined by Southern and Western blots. A dministration of 17-octadecynoic acid (17-ODYA), which is a P450 4A in hibitor, attenuated the constriction of third-order cremasteric arteri oles in response to elevation of superfusion solution PO2 from approxi mate to 3 to 5 mm Hg to approximate to 35 mm Hg. 17-ODYA had no effect on basal vascular tone or response of cremaster arterioles to vasoact ive compounds. These results demonstrate the existence of P450 omega-h ydroxylase activity and 20-HETE formation in the vasculature and paren chyma 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 se nsor in mammalian microcirculatory beds and to regulate arteriolar cal iber by generating 20-HETE in an oxygen-dependent manner.