Hyperangiotensinemia Induces Stem Cell/Progenitor Mobilization and De-Adhesion From BM Endothelial Cells Through AT2R Signaling and Inhibition of RhoA Activity
Authors: Chang Kyung-Hee , Nayak Ramesh C , Bezold Katie , Ficker Ashley , Roy Swarnava , Zhou Xuan , Pirman Megan , Dunn Susan , Zheng Yi , Malik Punam , Cancelas Jose A. 
Published: October 2019

Abstract 3466

Angiotensin II (Ang II) is a small peptide which acts as a major regulator of renal and cardiovascular function, controlling vessel pressure and the balance of water and electrolytes. Secondary hyperangiotensinemia induced by cardiac, liver or renal failure has been associated to increased circulation of hematopoietic stem cells and progenitors (HSC/P). Here we have elucidated the cellular and molecular role of Ang II in the regulation of HSC/P mobilization from the BM vascular niche(s). Chronic hyperangiotensinemia secondary to hypovolemia and endothelial barrier dysfunction was induced by endothelial (Tek-Cre) deletion of the gap junction protein connexin-43 (Cx43; EC-Cx43Δ/Δ mice) (Liao Y et al PNAS, 2001). Chronic hyperangiotensinemia results in significantly increased number of circulating hematopoietic progenitors (117.6±26.04 and 415.8±108.8 CFU-C/mL of blood for WT and Cx43 deficient EC, respectively, p<0.05) and stem cells (0.09±0.01 and 0.21±0.04 four-month competitive repopulating units/mL of blood for WT and Cx43 deficient EC, respectively, p<0.05) compared to wild-type (WT) counterparts. Administration of the ACE inhibitor enalapril reverses the increased level of plasma Ang II and circulating HSC/P to WT levels. Transient hyperangiotensinemia as a consequence of bolus administration of Ang II in vivo also results in increased mobilization of HSC/P. Administration of Ang II (1.44 mg/Kg intraperitoneally) in WT mice resulted in ∼60% increased circulation of HSC/P in PB by 15 minutes post-infusion which returned to basal levels by 30 minutes, indicating that the acute infusion of Ang II is responsible for HSC/P mobilization. HSC/P express both Ang II type-1 and type 2 receptors (AT1R and AT2R). Administration of Ang II to AT1R−/− mice induces HSC/P mobilization to similar levels to WT mice, but not in AT2R−/− mice, indicating that Ang II induces HSC/P mobilization through AT2R and not through AT1R. In order to determine the cellular basis of the effect of Ang II, we analyzed the adhesion of HSC/P to BMEC or BM stromal cells from WT or EC-Cx43Δ/Δ mice. Ang II stimulation induces de-adhesion of ∼30% HSC/P from either WT and Cx43-deficient ECs by 15 minutes after stimulation, but not from BM stromal cells, indicating that the interaction between HSC/P and BMEC is responsible for the Ang II-mediated de-adhesion effect and confirming that the deficiency of Cx43 in EC is not directly implicated in the mechanism of HSC/P de-adhesion. Ang II-induced HSC/P de-adhesion from BMEC is preceded (as early as 5 minutes post-stimulation) by decreased cortical F-actin polymerization in EC-adhered HSC/P. Coincidentally, the activation of the Rho-family member RhoA, as assessed by Rhotekin binding assay, and the activation of the RhoA effector myosin light chain (p-MLC), crucial for actomyosin assembly, were drastically decreased. Finally, inducible deficiency of RhoA in polyI:C treated Mx1Cre-RhoAf/f mice phenocopies the mobilization of HSC/P induced by hypeangiotensinemia. Altogether, our study demonstrates that Ang II induces EC-dependent HSC/P de-adhesion and mobilization through AT2R signaling and inhibition of RhoA activity and actomyosin rearrangements.

Disclosures:

No relevant conflicts of interest to declare.