HTATIP2 regulates arteriogenic activity in monocytes from patients with limb ischemia

JCI Insight. 2023 Oct 17:e131419. doi: 10.1172/jci.insight.131419. Online ahead of print.


Use of autologous cells isolated from elderly patients with multiple co-morbidities may account for the modest efficacy of cell therapy in patients with chronic limb threatening ischemia (CLTI). We aimed to determine whether pro-arteriogenic monocyte/macrophages (Mo/MΦs) from CLTI patients were functionally impaired and to demonstrate the mechanisms related to any impairment. Pro-arteriogenic Mo/MΦs isolated from CLTI patients were found to have an impaired capacity to promote neovascularization in vitro and in vivo compared with those isolated from healthy controls. This was associated with increased expression of human HIV-1 TAT interactive protein-2 (HTATIP2), a transcription factor known to suppress angiogenesis/arteriogenesis. Silencing HTATIP2 restored the functional capacity of CLTI Mo/MΦs which was associated with increased expression of arteriogenic regulators neuropilin-1 and angiopoietin-1, and their ability to enhance angiogenic (endothelial tubule formation) and arteriogenic (smooth muscle proliferation) processes in vitro. In support of the translational relevance of our findings, silencing HTATIP2 in pro-arteriogenic Mo/MΦs isolated from CLTI patients rescued their capacity to enhance limb perfusion in the ischemic hindlimb by effecting greater angiogenesis and arteriogenesis. Ex-vivo modulation of HTATIP2 may offer a strategy for rescuing the functional impairment of pro-angio/arteriogenic Mo/MΦs prior to autologous delivery and increase the likelihood of clinical efficacy.

Keywords: Angiogenesis; Cardiovascular disease; Macrophages; Monocytes; Therapeutics.