Short Reprogramming of Vascular Endothelium Reduces Blood Pressure in Hypertensive Mice
Reprogramming occurs in the early embryo, a conversion of adult germ cells into embryonic stem cells mediated by expression of the Yamanaka factors - canonically Oct3/4, Sox2, Klf4, and c-Myc. This is accompanied by a reset of age-related changes in gene expression, and a clearing out of cell damage and dysfunction. This process cannot fix everything, but in conjunction with the ability to selectively sacrifice embryonic cells with too great a burden of molecular damage, it does effectively ensure that the embryo is young even though its parents are old.
Partial reprogramming involves a short period of exposure to one or more of the Yamanaka factors or other reprogramming agents that can indirectly induce expression in one or more of the Yamanaka factors. The goal is to provoke the rejuvenation of gene expression observed in embryonic development without causing a loss of cell state and function. Researchers continue to work towards the most optimal way to achieve this outcome, but a number of approaches are presently in preclinical development. Along the way, researchers are producing proof of concept demonstrations for novel applications of reprogramming technologies, such as the one noted in today's open access preprint.
Small artery remodeling and endothelial dysfunction are hallmarks of hypertension. Growing evidence supports a likely causal association between cardiovascular diseases and the presence of endothelial-to-mesenchymal transition (EndMT), a cellular transdifferentiation process in which endothelial cells (ECs) partially lose their identity and acquire additional mesenchymal phenotypes. EC reprogramming represents an innovative strategy in regenerative medicine to prevent deleterious effects induced by cardiovascular diseases.
Using a partial reprogramming of ECs, via overexpression of Oct-3/4, Sox-2, and Klf-4 (OSK) transcription factors, we aimed to bring ECs back to a youthful phenotype in hypertensive mice. OSK overexpression induced partial EC reprogramming in vitro, and these cells showed endothelial progenitor cell (EPC)-like features with lower migratory capability. OSK treatment of hypertensive BPH/2J mice normalized blood pressure and resistance arteries hypercontractility, via the attenuation of EndMT and elastin breaks. OSK-treated human ECs from hypertensive patients showed high eNOS activation and NO production, with low ROS formation. Single-cell RNA analysis showed that OSK alleviated EC senescence and EndMT, restoring their phenotypes in human ECs from hypertensive patients.
Overall, these data indicate that OSK treatment and EC reprogramming can decrease blood pressure and reverse hypertension-induced vascular damage.