Caspase Lesions of PVN‐Projecting MnPO Neurons Blocks the Sustained Component of CIH‐Induced Hypertension in Adult Male Rats
Authors: Marciante Alexandria B , Wang Lei A , Little Joel T , Cunningham J. Thomas 
Published: June 2021

Obstructive Sleep Apnea (OSA) is characterized by cessations in respiration that leads to the development of chronic hypertension. Hypertension persists into the waking period even during normal respiratory patterns, and can increase a patient's risk factor for heart disease and stroke. Previous studies have shown that experimental models of chronic intermittent hypoxia (CIH) can produce a sustained hypertension similar to that associated with OSA. It has been proposed that the peripheral and CNS renin‐angiotensin systems contribute to hypertension associated with CIH. Our working hypothesis is that increased circulating angiotensin II feeds into the forebrain thereby increasing excitatory signaling through the hypothalamus and hindbrain, creating a vicious cycle. The median preoptic nucleus (MnPO) is an integrative forebrain region that contributes to blood pressure regulation. The MnPO has projections to the paraventricular nucleus (PVN) of the hypothalamus. The PVN contains pre‐autonomic centers that project to regions in the hindbrain that regulate sympathetic outflow. We hypothesized that by lesioning pathway specific projections from the MnPO to the PVN, we could attenuate the sustained component of CIH‐induced hypertension. For these experiments, adult male Sprague‐Dawley rats (250–300 g bw) were anesthetized with isoflurane and stereotaxically injected bilaterally in the PVN with a retrograde AAV containing Cre (AAV9.CMV.HI.eGFP‐Cre.WPRE.SV40) and with the caspase‐3 virus (AAV5‐flex‐taCasp3‐TEVp) or a control virus (AAV5‐hSyn‐DIO‐mCherry) in the MnPO. After 1 week recovery, rats were instrumented with aortic radio telemetry and allowed an additional week recovery following surgery. Rats were then moved to new homecages and underwent baseline recording for 7 days before undergoing our 7‐day CIH protocol. The control group exposed to CIH developed chronic hypertension, however, caspase lesions blunted the sustained hypertension developed during CIH. Brain tissue processed for FosB immunohistochemistry (IHC) showed decreased expression with caspase‐induced inhibition in the MnPO and downstream autonomic‐regulating nuclei in the PVN and rostral ventral lateral medulla (RVLM). CIH significantly increased plasma advanced oxidative protein products (AOPP) levels in controls. This increase in AOPP levels was blocked in caspase‐lesioned rats comparable to normoxic control concentrations. In situ hybridization experiments indicate a reduction in angiotensin type 1a receptors (AT1aR) expression in the caspase‐lesioned group exposed to CIH compared to CIH controls. The results indicate that MnPO neurons that project to the PVN play a significant role in blood pressure regulation and in the development of persistent CIH‐induced hypertension.Support or Funding InformationP01 HL088052 T32 AG020494This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.