4 factor-kappa B through redox-sensitive pathways, induces cell adhesion molecules as well as the chemokines MCP- 1 and interleukin-8. These molecules promote monocyte and T-lymphocyte adherence, invasion, and accumulation in atherosclerotic lesions [22, 24, 37, 82]. Taken together, these data support a local activated RAS in vessel walls that promotes inﬁltration of inﬂammatory cells into the vessel walls, which is an important feature of atherosclerosis. 3. The Function of Local Bone Marrow RAS We have recently reviewed the pathobiological aspects of local hematopoietic BM RAS [83]. The local haematopoi- etic bone marrow (BM) renin-angiotensin system (RAS) mediates pathobiological alterations of haematopoiesis in an autocrine/paracrine/intracrine fashion [84]. Recent data further indicated the existence of angiotensin-converting enzyme (ACE) in human primitive lympho-haematopoietic cells, embryonic, foetal, and adult haematopoietic tissues [85, 86]. Human umbilical cord blood cells also express renin, angiotensinogen, and ACE mRNAs [87, 88]. As ACE and other angiotensin peptides function in human haematopoietic stem cells (HSCs) throughout haematopoi- etic ontogeny and adulthood [85, 86], local RAS could also have a function in HSC plasticity, and the development of haematological neoplastic disorders [83, 89, 90]. The presence of ACE on leukaemic blast cells within leukaemic BM [91, 92], on erythroleukaemic cells [93], ACE-expressing macrophages in lymph nodes of Hodgkin disease [94], renin activity in leukaemic blasts [95, 96], Ang II as an autocrine growth factor for AML [97], increased renin gene activ- ity during NUP98-HOXA9-enhanced blast formation [98], higher levels of BB9/ACE (+) AML isoforms [85], and altered JAK-STAT pathway as a link between RAS and leukaemia [83, 99] indicated the wide pathobiological aspects of local BM RAS. Local hematopoietic BM RAS particularly mediates pathogenesis of myeloproliferative disorders (MPDs) [83]. JAK-STAT pathway represents the point of crosstalk between the upstream local BM RAS and neoplastic hematopoiesis [83, 99]. Abnormally enhanced expressions of the main RAS components in MPD are downregulated by the tar- geted therapy, imatinib mesylate [100]. JAK1 and JAK2 inhibitor, INCB018424, decreased clonal neoplastic cells and downregulated inﬂammatory responses in MPD [101]. Since neoplasia and inﬂammation are the main pivotal actions of hematopoietic BM RAS, which is the upstream controlling pathway of JAK-STAT signaling [83, 102]; direct eﬀects of INCB018424 on RAS shall be further searched to understand its clinically translated pleiotropic molecular engagements. The comparable biological actions of local RASs throughout the human body (including myocardium, pancreas, pituitary gland, ovary, and kidney) represent the true basis for the search of their prominence in tissue functions [83]. Interestingly a previous study provided by Savary et al. [103] demonstrated the presence of a locally active RAS in the yolk sac and possible RAS-dependent participation of ACE in the modulation of early yolk sac erythropoiesis. Moreover the discovery that ACE/CD143 marks primitive Cardiology Research and Practice embryonic hemangioblasts raised the probability that the versatile RAS plays a crucial role in regulating the earliest stages of human hematoendothelial diﬀerentiation, as it does in avian embryos. Zambidis et al. [104] successfully demonstrated a dramatic upregulation of AT2R during expansion of human embryoid body (hEB)-derived ACE+ hemangioblasts, which proposes an exclusive role for the RAS in guiding the early developmental phases of human angio- hematopoiesis [105–107]. Furthermore they found that hEB- derived blast-colony-forming cell could be targeted to dif- ferentiate into either hematopoietic or endothelial progeny by manipulating signaling pathways normally mediated by the RAS. And also manipulation of angiotensin II signaling with either AT1R or AT2R speciﬁc inhibitors toward either endothelium, or multipotent hematopoietic progenitors, resulted in obvious deviations of hEB diﬀerentiation [105]. 4. Local Haematopoietic Bone Marrow RAS in the Pathogenesis of Atherosclerosis There is a close interrelationship between hematopoietic bone marrow RAS and the cardiac RAS [105, 106]. Myocar- dial tissue repair via hematopoietic stem cell plasticity may represent a point of crosstalk between local cardiac RAS and hematopoietic RAS (Figure 1) [89, 108]. Inﬂammatory medi- ators particularly macrophages/monocytes, neutrophils and T-lymphocytes play a central role in all phases of atheroscle- rosis. Atherosclerotic lesions are initiated by endothelial cell damage, followed by monocyte/macrophage adhesion and invasion as well as smooth muscle cell migration and proliferation [109, 110]. In this perspective, restenosis after angioplasty shares a common pathophysiological process with atherosclerosis, where endothelial injury followed by impaired endothelialization [111, 112]. Previously it has been believed that only migration and proliferation of adjacent endothelial cells in the vessel wall causes re- endothelialization, but afterwards it has been proved that endothelial progenitor cells derived from bone marrow (BM) also participate in this course [113–115]. A local RAS in BM has a possible role in endothelial progenitor cell biology caus- ing neovascularization. Recently it has been demonstrated that RAS activation stimulates endothelial progenitor cell proliferation and neovascularization [26, 116]. Strawn et al. was the ﬁrst to propose a lipid-angiotensin system connection within the BM that accounts for the predisposition of immune cells to home to coronary arteries and initiate atherosclerosis [117, 118]. Their data supported a positive regulatory role of plasma LDL on AT1R-mediated haematopoetic stem cell diﬀerentiation and the production of proatherogenic monocytes which may explain in part hypercholesterolemia-induced inﬂammation as well as the anti-inﬂammatory and antiatherosclerotic eﬀects of AT1R blockers. This innovative theory combines the former lipid hypotheses and allows for an immunological activation concept that begins as early as changes in the BM that result in the generation of activated circulating monocytic phenotypes that participate in atherogenesis. The “bone marrow response-to-lipid” hypothesis incorporates