Multi-Organ Comparative Transcriptomic Study on Short-Term and Long-Term Hypoxia Adaptation in Cattle.

Highland Tibetan cattle have evolved unique hypoxic adaptation capabilities from their lowland ancestors; however, the mechanisms that distinguish short-term acclimatization from long-term genetic adaptation remain poorly understood. In this study, we integrated hematological assays and multi-organ transcriptomic analyses across three groups: highland Tibetan cattle (long-term adaptation), highland-acclimatized Holsteins (short-term acclimatization), and lowland Holsteins (controls). Hematologically, highland-acclimatized Holsteins displayed elevated red blood cell count, hemoglobin level, and blood viscosity, consistent with compensatory responses to hypoxia. In contrast, Tibetan cattle maintained lower and more stable hematological parameters, reflecting a blunted adaptive strategy shaped by long-term natural selection. Transcriptomic analysis revealed tissue-specific response to hypoxia: the heart underwent metabolic reprogramming, the liver shifted from metabolic compensation toward immune homeostasis, and the lung exhibited limited transcriptional changes associated with enhanced oxygen exchange efficiency. Pathway analysis and immunohistochemistry implicated GNB1 in PI3K-AKT-associated angiogenic responses to hypoxia. Furthermore, hepatic SLAMF7 upregulation and recombinant SLAMF7 activity against S. aureus and E. coli suggested a potential role in long-term immune resilience. Collectively, our findings clarify the dynamic transition from short-term physiological stress responses to long-term genetic adaptation in cattle under high-altitude hypoxic conditions, providing novel insights into the hypoxic adaptation mechanisms of ruminants.