Cerebral artery alpha-1 AR subtypes: high altitude long-term acclimatization responses.
In response to hypoxia and other stress, the sympathetic (adrenergic) nervous system regulates arterial contractility and blood flow, partly through differential activities of the alpha1 (α1) - adrenergic receptor (AR) subtypes (α1A-, α1B-, and α1D-AR). Thus, we tested the hypothesis that with acclimatization to long-term hypoxia (LTH), contractility of middle cerebral arteries (MCA) is regulated by changes in expression and activation of the specific α1-AR subtypes. We conducted experiments in MCA from adult normoxic sheep maintained near sea level (300 m) and those exposed to LTH (110 days at 3801 m). Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10-5 M phenylephrine (PHE). LTH-acclimatized cerebral arteries also demonstrated a statistically significant (P<0.05) inhibition of PHE-induced contractility in the presence of specific α1-AR subtype antagonists. Importantly, compared to normoxic vessels, there was significantly greater (P<0.05) α1B-AR subtype mRNA and protein levels in LTH acclimatized MCA. Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype. Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function.
Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America; Epigenuity LLC, Loma Linda, California, United States of America.
Ravi
R
Goyal
Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America; Epigenuity LLC, Loma Linda, California, United States of America.
Dipali
D
Goyal
Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America; Epigenuity LLC, Loma Linda, California, United States of America.
Nina
N
Chu
Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America; Epigenuity LLC, Loma Linda, California, United States of America.
Jonathan
J
Van Wickle
Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America; Epigenuity LLC, Loma Linda, California, United States of America.
Lawrence D
LD
Longo
D000064:Acclimatization / Q000502:physiology*; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000531:Altitude; D000818:Animals; D004146:Dioxanes / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics* / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction; D046509:Tissue Culture Techniques
D058646:Adrenergic alpha-1 Receptor Agonists; D004146:Dioxanes; D020033:Protein Isoforms; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009638:Norepinephrine