Caspase lesions of PVN-projecting MnPO neurons block the sustained component of CIH-induced hypertension in adult male rats

Abstract

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 Information P01 HL088052 T32 AG020494 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

“…The PVH also originates sympathetic signaling to other organs, including the heart (Nunn et al, 2011). The POA→PVH pathway has been implicated in autonomic cardiovascular and renal regulation (Frazier et al, 2020; Llewellyn et al, 2012; Marciante et al, 2020; McKinley et al, 2015; Sawchenko and Swanson, 1983; Stocker and Toney, 2005), but less in Tb regulation. We now show that POA BRS3 →PVH neurons regulate Tb, HR, and MAP through the sympathetic nervous system.…”

Recent Advances in Studies on the Role of Neuroendocrine Disorders in Obstructive Sleep Apnea–Hypopnea Syndrome-Related Atherosclerosis

“…PVN integrates information in an ascending order both from the MnPO and the NTS. 90,91 Glutamatergic neurons There was a significant relationship between OSAHS severity and coronary atherosclerotic plaque volume. 47 Coronary heart disease incidence is higher in patients with OSAHS than in non-OSAHS individuals.…”

“…PVN integrates information in an ascending order both from the MnPO and the NTS. 90 , 91 Glutamatergic neurons in PVN transmit information to RVLM and regulate sympathetic outflow. 92 Most activated PVN neurons contain corticotropin-releasing hormones (CRHs).…”

AT1a-dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia

“…Gel foam was packed into the burr hole, and absorbable antibiotic sutures were used to close the incision site and minimize postsurgical infection. In a separate group of rats, DIO-ClopHensorN was injected into the MnPO and a retrograde virus expressing Cre was injected into the PVN (bilateral injections; AP = À1.8, ML = ±0.4, DV = À7.6) as described (14). All the rats were given at least 2 wk to recover and to allow for the expression of viral constructs before the slice preparation.…”

“…Moreover, blockade of AT1a receptors in the MnPO prevents the CIHinduced increase in DFosB as well as the persistent increase in blood pressure associated with CIH (9). More recently, the role of the MnPO in CIH hypertension was tested by injecting the paraventricular nucleus of the hypothalamus (PVN) with a retrograde adeno-associated viral vector expressing CRE and injecting the MnPO with an adeno-associated viral vector expressing a Cre-dependent caspase-3 (14). This approach effectively lesioned PVN-projecting MnPO neurons and blocked the development of the sustained component of CIH hypertension expressed during normoxia.…”