Aging-Induced Down-Regulation of PKA/BKCa Pathway in Rat Cerebral Arteries

The incidence of cerebrovascular diseases increases significantly with aging. This study aimed to test the hypothesis that aging may influence the protein kinase A (PKA)-dependent vasodilation via RyR/BKCa pathway in the middle cerebral arteries (MCA). Male Sprague-Dawley rats were randomly divided into control (4-6 month-old) and aged (24-month-old) groups. The functions of MCA and ion channel activities in smooth muscle cells were examined using myograph system and patch-clamp. Aging decreased the isoproterenol/forskolin-induced relaxation in the MCA. Large-conductance Ca2+-activated-K+ (BKCa) channel inhibitor, iberiotoxin, significantly attenuated the forskolin-induced vasodilatation and hyperpolarization in the young group, but not in the aged group. The amplitude and frequency of spontaneous transient outward currents (STOCs) were significantly decreased in the aged group. Single channel recording revealed that the mean open time of BKCa channels were decreased, while an increased mean closed time of BKCa channels were found in the aged group. The Ca2+/voltage sensitivity of the channels was decreased accompanied by reduced BKCa alpha and I31-subunit, the expression of RyR2, PKA-C alpha and PKA-CI3 subunits were also declined in the aged group. Aging induced down-regulation of PKA/BKCa pathway in cerebral artery in rats. The results provides new information on further understanding in cerebrovascular diseases resulted from age-related cerebral vascular dysfunction.

Automated summary

The incidence of cerebrovascular diseases increases significantly with aging. This study found that aging may influence the PKA-dependent vasodilation via the RyR/BKCa pathway in the middle cerebral arteries. In aged rats, the PKA/BKCa pathway was down-regulated, leading to decreased relaxation of the arteries and reduced BKCa channel activity. These findings provide new insights into the age-related cerebral vascular dysfunction and cerebrovascular diseases.