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

Abstract 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 cattle groups: highland Tibetan cattle (representing long-term genetic adaptation), highland-acclimatized Holstein cattle (representing short-term acclimatization), and lowland Holstein cattle (serving as controls). Hematologically, highland-acclimatized Holsteins displayed elevated red blood cell count, hemoglobin level, and blood viscosity, which constitutes a short-term compensatory stress response 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 hypoxic response patterns: the heart underwent metabolic reprogramming to support sustained hypoxic adaptation, the liver shifted its functional focus from metabolic compensation to the regulation of immune homeostasis, and the lung exhibited limited transcriptional changes associated with enhanced oxygen exchange efficiency. Immunohistochemical validation demonstrated that GNB1, a key hypoxia-responsive gene, mediates hypoxic adaptation through angiogenesis regulated by the PI3K-AKT pathway. Furthermore, the immune-related gene SLAMF7 was significantly upregulated in the liver of Tibetan cattle, and its recombinant protein exhibited broad-spectrum antibacterial activity, highlighting its critical role in long-term immune adaptation. 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.