Genetic basis of impaired myogenic response and cerebral blood flow autoregulation FHH rats

Abstract

This study examined the effect of transfer of a small region from chromosome 1 (Chr 1) of the Brown Norway (BN) rat (FHH.1BN AR+ strain) into the Fawn Hooded Hypertensive (FHH) rat genetic background on autoregulation of cerebral blood flow (CBF) and the myogenic response of isolated perfused middle cerebral arteries (MCA). FHH rats exhibited poor autoregulation measured by laser Doppler flowmetry and CBF rose by 50% when perfusion pressure was increased from 100 to 150 mmHg. Autoregulation of CBF was completely restored in the AR+ strain. The diameter of isolated middle cerebral artery (MCA) of FHH rats increased by 10% when transmural pressure was increased from 40 to 140 mmHg. In contrast, the diameter of the MCA fell from 127±16 to 65±14 μm in the AR+ strain when pressure was increased over this range. FHH rats exhibited a much more prolonged hyperemia and larger infarct than that seen in the AR+ strain following ischemia/reperfusion. These results indicate that a gene that plays a critical role in the myogenic response of cerebral arteries lies within this critical 2.6 Mb region containing just 11 genes and that transfer of this region restores autoregulation of CBF and reduces infarct size following ischemia/reperfusion injury. The impaired myogenic response is likely due to hyperpolarization of VSM cells due to increased BK channel activity. NIH HL36279, DK79306, HL59996.