Inducible Deletion of Endothelial Hba1 Significantly Reduces Exercise Fitness in Mice

Abstract

Hemoglobin (Hb) alpha is uniquely expressed in the endothelial cells of resistance arteries. The same protein is generated by both Hba1 and Hba2 genes. We have shown that siRNA knockdown of endothelial Hba1 decreases Hb alpha protein, and increases NO signaling in the vascular wall. Furthermore, pharmacologic inhibition of the interaction between endothelial Hb alpha and endothelial nitric oxide synthase reduces blood pressure. To further study the role of endothelial Hb alpha, we have produced a novel genetically modified mouse in which exons 2 and 3 of the Hba1 gene are flanked by loxP sites (Hba1fl/fl). We have crossed the Hba1fl/fl mice with a Cdh5‐Cre/ERT2+ mice to produce a tamoxifen‐inducible genetic model in which Hba1 can be temporally deleted from endothelial cells (EC Hba1fl/fl). We compared EC Hba1fl/fl with Hba1−/− (global deletion of Hba1) and found both mice exhibit reduced expression of Hba protein in skeletal muscle endothelial arteries and arterioles. However, while Hba1−/− mice showed significant decreases in several red blood cell parameters including hemoglobin concentration, hematocrit, erythrocyte count, red cell volume, and red cell hemoglobin, EC Hba1fl/fl red blood cell parameters were all unchanged. In order to test roles of endothelial alpha globin in hypoxic blood flow control, we used a treadmill running test to measure acute endurance capacity, as well as long‐term measurement of voluntary running volume in running wheel‐equipped cages. We found that in both experimental conditions, male EC Hba1fl/fl mice had a significant reduction in exercise capacity, mirroring the exercise phenotype of Hba1−/− mice. We conclude that endothelial Hba1 is an important regulator of vascular function and skeletal muscle performance.Support or Funding InformationAmerican Heart Predoctoral Fellowship #16PRE30240007, NIH R01 HL088554This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.