Life-sustaining responses to hypoxia rely on the transcription factor, Hypoxia Inducible Factor-1 (HIF-1). Under hypoxia, HIF-1 accumulates and regulates multifaceted cellular responses. However, many underlying mechanisms of HIF-1 regulation are incompletely understood. Previous studies suggest a link between HIF-1 and beta-adrenergic receptors (ßAR). Here, we interrogated the role of ßARs in hypoxia responses by ß-blocker treatment of mice with hypoxia-inducible erythropoiesis. ß-blocker suppressed renal accumulation of HIF-1a, erythropoietin production and the generation of erythroid progenitor cells. Likewise, ß-blocker treatment of human endothelial cells attenuated HIF-1a accumulation and binding to target genes under hypoxia, and subsequent downstream gene expression. Consistently, ß-agonist increased HIF-1a accumulation in a dose- and time-dependent manner, an effect that was blocked by both ß1- and ß2-blockers, indicating a general property of this receptor class. ßAR signal transduction involves cyclic adenosine monophosphate (cAMP)-activated protein kinase A (PKA) and G protein-coupled receptor kinases (GRK). Direct activation of cAMP/ PKA pathways did not increase HIF-1a accumulation, and inhibition of PKA did not suppress HIF-1a by hypoxia. In contrast, pharmacological inhibition of GRK, or genetic mutation of ßAR that impairs GRK phosphorylation, blocked hypoxia-mediated HIF-1a accumulation. Mass spectrometry analyses revealed a unique hypoxia ßAR phosphorylation barcode different from the classical agonist. These findings identify an unknown role of ßAR in hypoxia responses. Another determinant of HIF-1 regulation is nitric oxide, a potent vasodilator. A natural experiment of genetically similar Ethiopians at high altitude (>3000 m), the Amhara and Oromo, revealed a dampened hemoglobin response in Amhara compared to Oromo. We hypothesized that Amhara highlanders offset their dampened hemoglobin response with the vascular nitric oxide response. We identified high levels of urinary nitrate and its bioactive signal molecule cyclic guanosine monophosphate (cGMP) in high-altitude Amhara, but not Oromo. Consistently, high-altitude Amhara have lower diastolic blood pressure than Oromo, an indicator of vasomotor tone. Both Amhara and Oromo maintained the amount of oxyhemoglobin at high altitudes, but the high-altitude Oromo suffered a much higher deoxyhemoglobin level. In conclusion, high-altitude Amhara offset a dampened hemoglobin response with the vasodilatory nitric oxide, whereas the Oromo mount a bigger hemoglobin response at the cost of circulating deoxyhemoglobin.