Molecular mechanisms controlling nutritive blood flow: role of cytochrome P450 enzymes

This short review summarizes the potential role of cytochrome P450 (P450) i n regulating blood flow in the brain tissue and in the skeletal muscle. We provide data showing that pressure-induced myogenic activity in the brain i s largely responsible for autoregulation of CBF. This myogenic response to pressure is maintained, in part, by 20-HETE formation in arterial muscle ce lls through a P450 omega-hydroxylase coded for by a P450 4A cDNA. Autoregul ation of CBF is a hallmark of the cerebral circulation and provides adequat e nutritive blood flow despite large fluctuations in arterial pressure. Giv en the importance of oxidative metabolism in the brain, support of neuronal activity is mediated by functional hyperaemia to active neurones providing adequate delivery of oxidative substrate. We provide data demonstrating th at this functional hyperaemia in the brain is regulated by astrocytes which sense neural activity and release dilator metabolites which shunt blood fl ow to active neurones. One of the metabolites released by astrocytes in thi s regard are epoxygenated products of arachidonic acid (AA) formed by P450 enzymes. These AA metabolites of P450 enzymes are epoxyeicosatrienoic acid (EETs). One of these P450 enzymes is coded by a 2C11 cDNA present in astroc ytes. Furthermore, astrocytes are capable of inducing capillary angiogenesi s which appears to be mediated, in part, by P450-derived EETs.