Prenatal Hypoxia Leads to Increased Muscle Sympathetic Nerve Activity, Sympathetic Hyperinnervation, Premature Blunting of Neuropeptide Y Signaling, and Hypertension in Adult Life

Abstract

Abstract-Adverse conditions prenatally increase the risk of cardiovascular disease, including hypertension. Chronic hypoxia in utero (CHU) causes endothelial dysfunction, but whether sympathetic vasoconstrictor nerve functioning is altered is unknown. We, therefore, compared in male CHU and control (N) rats muscle sympathetic nerve activity, vascular sympathetic innervation density, and mechanisms of sympathetic vasoconstriction. In young (Y)-CHU and Y-N rats (≈3 months), baseline arterial blood pressure was similar. However, tonic muscle sympathetic nerve activity recorded focally from arterial vessels of spinotrapezius muscle had higher mean frequency in Y-CHU than in Y-N rats (0.56±0.075 versus 0.33±0.036 Hz), and the proportions of single units with high instantaneous frequencies (1-5 and 6-10 Hz) being greater in Y-CHU rats. Sympathetic innervation density of tibial arteries was ≈50% greater in Y-CHU than in Y-N rats. Increases in femoral vascular resistance evoked by sympathetic stimulation at low frequency (2 Hz for 2 minutes) and bursts at 20 Hz were substantially smaller in Y-CHU than in Y-N rats. In Y-N only, the neuropeptide Y Y1-receptor antagonist BIBP3226 attenuated these responses. By contrast, baseline arterial blood pressure was higher in middle-aged (M)-CHU than in M-N rats (≈9 months; 139±3 versus 126±3 mm Hg, respectively). BIBP3226 had no effect on femoral vascular resistance increases evoked by 2 Hz or 20 Hz bursts in M-N or M-CHU rats. These results indicate that fetal programming induced by prenatal hypoxia causes an increase in centrally generated muscle sympathetic nerve activity in youth and hypertension by middle age. This is associated with blunting of sympathetically evoked vasoconstriction and its neuropeptide Y component that may reflect premature vascular aging and contribute to increased risk of cardiovascular

Developmental Programming of Hypertension

“…Blood pressure was not elevated at this age, but blood pressure was increased by 9 months of age in male offspring exposed to prenatal hypoxia relative to male control (23) suggesting that exposure to hypoxia during fetal life programs an increase in basal muscle SNA that precedes the development of increased blood pressure. Despite the increase in sympathetic nerve density, vasoconstrictor responses to sympathetic nerve stimulation were blunted in male prenatal hypoxia offspring at 3 months of age relative to age-matched control counterparts (23). Blockade of the neurotransmitter neuropeptide Y attenuated these responses in male control offspring at 3 months of age with no effect on vasoconstrictor responses to sympathetic nerve stimulation in prenatal hypoxia counterparts (23).…”

“…This study published in Hypertension reported that frequency of single unit muscle SNA and sympathetic innervation of the tibial arteries were increased at 3 months of age in male offspring exposed to prenatal hypoxia (23). Blood pressure was not elevated at this age, but blood pressure was increased by 9 months of age in male offspring exposed to prenatal hypoxia relative to male control (23) suggesting that exposure to hypoxia during fetal life programs an increase in basal muscle SNA that precedes the development of increased blood pressure. Despite the increase in sympathetic nerve density, vasoconstrictor responses to sympathetic nerve stimulation were blunted in male prenatal hypoxia offspring at 3 months of age relative to age-matched control counterparts (23).…”

“…Although aging in humans is associated with an increase in sympathetic outflow to the peripheral tissues, responsiveness to sympathetic stimulation decreases with aging (22). Therefore, Rook et al investigated whether temporal changes in muscle SNA were associated with increased blood pressure in male offspring exposed to prenatal hypoxia (23). This study published in Hypertension reported that frequency of single unit muscle SNA and sympathetic innervation of the tibial arteries were increased at 3 months of age in male offspring exposed to prenatal hypoxia (23).…”

“…Therefore, Rook et al investigated whether temporal changes in muscle SNA were associated with increased blood pressure in male offspring exposed to prenatal hypoxia (23). This study published in Hypertension reported that frequency of single unit muscle SNA and sympathetic innervation of the tibial arteries were increased at 3 months of age in male offspring exposed to prenatal hypoxia (23). Blood pressure was not elevated at this age, but blood pressure was increased by 9 months of age in male offspring exposed to prenatal hypoxia relative to male control (23) suggesting that exposure to hypoxia during fetal life programs an increase in basal muscle SNA that precedes the development of increased blood pressure.…”

Elevated levels of neuropeptide Y in preeclampsia: A pilot study implicating a role for stress in pathogenesis of the disease

“…Previous reports suggested that elevated systemic levels of NPY in PE reflect SNS hyperactivity resulting in the long-lasting vasoconstriction and hypertension found in this condition. Such SNS overactivity can be triggered by uterine blood flow restriction, as hypoxia is a strong SNS activator (Rook et al , 2014). However, there are also epidemiological data indicating associations of psychosocial stress in pregnancy with increased risk of preeclampsia, suggesting that the elevated NPY levels observed specifically in MTPE may reflect maternal chronic stress (Klonoff-Cohen et al , 1996; Kurki et al , 2000; Paarlberg et al , 1995; Salvador-Moysen et al , 2012; Sandman et al , 1997; Wadhwa et al , 1996).…”