Abstract
The renin-angiotensin system (RAS) has long been a known endocrine system that is involved in regulation of blood pressure and fluid balance. Over the last two decades, evidence has accrued that shows that there are local RAS that can affect cellular activity, tissue injury, and tissue regeneration. There are locally active ligand peptides, mediators, receptors, and signaling pathways of the RAS in the bone marrow (BM). This system is fundamentally involved and controls the essential steps of primitive and definitive blood-cell production. Hematopoiesis, erythropoiesis, myelopoiesis, thrombopoiesis, formation of monocytic and lymphocytic lineages, as well as stromal elements are regulated by the local BM RAS. The expression of a local BM RAS has been shown in very early, primitive embryonic hematopoiesis. Angiotensin-converting enzyme (ACE-1, CD143) is expressed on the surface of hemangioblasts and isolation of the CD143 positive cells allows for recovery of all hemangioblast activity, the first endothelial and hematopoietic cells, forming the marrow cavity in the embryo. CD143 expression also marks long-term blood-forming CD34+ BM cells. Expression of receptors of the RAS is modified in the BM with cellular maturation and by injury. Ligation of the receptors of the RAS has been shown to modify the status of the BM resulting in accelerated hematopoiesis after injury. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive and definitive hematopoiesis as well as modification of BM recovery by administration of exogenous ligands of the RAS. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of BM recovery after injury as well as neoplastic disorders.
Highlights
The first evidence that there are effects of the renin-angiotensin system (RAS) on bone marrow (BM) and hematopoiesis resulted from clinical use of therapeutics that modify the production/action of angiotensin II (A-II)
These observations led to the hypothesis in the mid-1990s that there is a local RAS in the BM that is involved in the regulation of hematopoiesis
Administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to 2-day-old embryos resulted in a significantly lower hematocrit in treated embryos than in control embryos. These results show that the RAS modulates blood-island differentiation during the primitive yolk-sac erythropoiesis [35]
Summary
The first evidence that there are effects of the renin-angiotensin system (RAS) on bone marrow (BM) and hematopoiesis resulted from clinical use of therapeutics that modify the production/action of angiotensin II (A-II). In these patients, there are anecdotal reports and studies showed that ACE inhibitors, and angiotensin receptor blockers (ARBs) reduce hematocrit levels in post-transplantation erythrocytosis [5,6,7]. A reduction in hemoglobin concentrations was reported in hypertensive patients treated with ARBs compared with patients treated with β-blockers or calcium antagonists [8, 9]. These observations led to the hypothesis in the mid-1990s that there is a local RAS in the BM that is involved in the regulation of hematopoiesis.
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