Circulating monocytes have been classified into different subsets based on the chemokine receptors they express and the presence of specific surface molecules (25). In humans, monocytes are classified according to the presence of CD14 and CD16 on their surface (26, 27). CD14⁺⁺CD16^– are known as classical monocytes, which are the most abundant in the bloodstream. Alternatively, CD14⁺⁺CD16⁺ are referred as intermediate monocytes and, CD14⁺⁺CD16⁺⁺, as non-classical patrolling monocytes. However, in mice, only two subsets have been identified (28). One of these populations corresponds to CD14⁺ CD62 ligand (CD62L)⁺ CC-chemokine receptor 2 (CCR2)⁺, which is known as LY6C^hi or inflammatory monocytes (23, 29). The second population is similar to CD16⁺CCR2^– monocytes in humans, and it is known as LY6C^low or patrolling monocytes, that express high levels of CX3C-chemokine receptor 1 (CX3CR1) and low levels of CCR2 and LY6C (24).

Recruitment of LY6C^hi monocytes from the bone marrow is mediated by the binding of CC-chemokine ligand 2 (CCL2) (30), also known as monocyte chemoattractant protein-1 (MCP-1), and CCL7 (or MCP-3) to CCR2 (31, 32). Most cells express CCL2 in response to pro-inflammatory cytokines in infections (33). Thus, after many infections, circulating levels of CCL2 increase in both the serum and inflamed tissues, where CCL2 binds to CCR2 that is expressed on certain cell types (23). CCL7 expression is also stimulated by infections and contributes to LY6C^hi monocyte recruitment (23). Both CCL2 and CCL7 have shown important roles on monocyte recruitment, although the mechanism of action is still unclear (31, 32). Conversely, recruitment and survival of LY6C^low monocytes is mediated by the binding of CX3C-chemokine ligand 1 (CX3CL1), also known as fractalkine (FKN), to CX3CR1 (34).

Monocytes also express other CC-chemokine receptors, such as CCR1 and CCR5 (35) that bind to various cytokines including CCL3 (also known as MIP1α) and CCL5 (also denominated RANTES) (29). Both receptors display specialized roles in monocyte recruitment. CCR1 mediates monocyte arrest in fluid shear stress generated by blood flow. CCR5 is involved in monocyte spreading. They both contribute to transendothelial chemotaxis towards CCL5 gradients (36). However, none of these receptors have shown redundancy in cell recruitment during inflammation, which has implications in the development and progression of many diseases, including atherosclerosis and rheumatoid arthritis (29, 37, 38). This may be a consequence of the wide spectrum of cells expressing these chemokine receptors (39), so determining the specific role they play in monocyte recruitment is complex (23).

Other chemokines have also been suggested to play a role on monocyte recruitment ( Table 1 ). Some examples are CCR6 (42), CCR7 (43), CCR8 (44), and CXC-chemokine receptor 2 (CXCR2) (45). Circulating monocytes express low levels of CCR6 and do not respond to CCL20, which explains that CCR6 does not display a significant role on the extravasation of monocytes from the circulation to the tissues, but it does on the migration or function of monocytes in inflammation (46, 47).

Monocyte migration to inflammatory sites is a multistep process involving many molecules ( Table 2 ). The initial tethering and rolling of monocytes along the inflamed endothelium are mediated by selectins. Selectins are cell-surface proteins that interact with glycoprotein ligands to allow monocytes to bind weakly and reversibly to cytokine-activated ECs (24, 62). The selectins involved in this process are L-selectin (CD62L), P-selectin (CD62P) and E-selectin (CD62E). L-selectin, expressed on circulating monocytes, interacts with specific fucosylated sialoglycoproteins expressed on lymph node venules and inflamed or injured vascular endothelium (48, 49, 63). P-selectin glycoprotein ligand-1 (PSGL-1), P-selectin glycoprotein ligand-1 (PSGL-1), expressed on monocytes, interacts with P-selectinand E-selectin expressed on inflamed endothelium (50). Then, PSGL-1 can also interact with circulating monocytes expressing L-selectin and amplify the monocyte recruitment (52). This initial adhesion mediated by selectins reduces the rolling velocity of monocytes and allows the cells to interact with chemokines that are bound to inflamed ECs (64). ECs are activated by inflammatory cytokines such as TNF-α or IL-1β. This activation induces the expression of adhesion molecules such as E- and P-selectin, intercellular adhesion molecule 1 (ICAM1/CD54) and vascular cell-adhesion molecule 1 (VCAM1/CD106) that participate in monocyte migration (65).

Chemokines can bind to transmembrane heparan sulphate proteoglycans on the luminal surface of vascular ECs to be presented to monocytes (66). The main proteoglycans identified as chemokine-binders include CD44, syndecan 1 and syndecan 4 (which bind CCL5) and syndecan 2 (which interacts with CXCL8) (66). Chemokines bind to G-protein-coupled receptors (GPCRs) of monocytes and induce inside-out signals that result in integrin activation. GPCRs activate specific Gi and Gq heterotrimeric proteins and their downstream effectors. Two key guanosine triphosphatases (GTPases), RhoA and Rap1, have been implicated in chemokine activation of integrins (67, 68). Rap1 is a small GTPase of the RAS family that cycles between an inactive GDP-bound form and an active GTP-bound form (54). Activated Rap1 binds RAPL, and the complex activates the integrin by binding to the alpha-chain of integrin (69). Rap1 also binds to Rap-interacting adapter molecule (RIAM), which recruits talin (70). Talin is a cytoskeletal protein that binds to the beta-chain of the integrins, thereby triggering integrin activation (71, 72). Integrin activation induces conformational changes initiated at the alpha and beta subunit cytoplasmic tails and transmitted to their extracellular domain (73). This inside-out signaling activates integrins such as lymphocyte function-associated antigen 1 (LFA1; also known as αLβ2-integrin and CD11a–CD18) and very late antigen 4 (VLA4; also known as α4β1-integrin, and CD49d–CD29). Activated β2 and α4-integrins ensure the arrest of monocytes and the formation of firm adhesions by binding ICAM1 and VCAM1 respectively, which are expressed by inflamed endothelial cells (54) [ Table 2 ]. Other integrins such as the macrophage receptor 1 (Mac1; also known as αMβ2-integrin and CD11b–CD18) and αXβ2-integrin are also activated via this signaling pathway (56).

The firm adhesion of a monocyte to the vascular endothelium results in a morphological and phenotypical change known as polarization ( Figure 1 ) (74). Polarization involves the formation of two different regions: the lamellipodia at the leading edge and the uropod at the tail of the monocyte (74). Polarization involves reorganization of the cytoskeletal proteins, intracellular regulatory molecules, chemoattractant receptors and integrins (75). F-actin changes from radially symmetric around the cell to accumulated in the leading edge (76). Chemokine receptors redistribute to the leading edge, while other adhesion molecules, such as CD44, accumulate at the uropod (75). In addition, high affinity integrins mobilize to the leading edge and low affinity integrins to the uropod (54). Attachment of integrins at the leading edge and detachment at the uropod occurs during migration (77). Several signaling pathways contribute to polarization including Rho family GTPases, GTPase Rap1, protein kinases, and lipid kinases (75). GTPase Rap1 has also been described as a key molecule in integrin activation and redistribution during leukocyte polarization (54). RAP1 and RAPL control the polarized recruitment of integrin clusters to the lamellipodium (69). RHOA, another member of the RAS superfamily, also participates in integrin clustering by activating RHO-associated coiled-coil containing protein kinase 1 (ROCK1), which phosphorylates the actin cytoskeleton (24). GPCR downstream signals also activate PI3K, which participates in monocyte polarization via activation of the atypical protein kinase C-ζ (PKC-ζ) and formation of the polarity complex (consisting of partitioning defective 6 (PAR6)/PKC-ζ/lethal giant larvae, LGL). PKC-ζ signaling facilitates integrin lateral mobility (after integrin is in its high affinity form) due to the mobilization of new lipid membrane to the leading edge (78). The polarized recruitment of integrins clusters to the lamellipodium results in polarized adhesion and then migration (24). After polarization, monocytes migrate to the interendothelial junctions.

Adjacent ECs are connected by a wide array of endothelial junctions: tight junctions, adherens junctions and gap junctions (79). Tight and adherens junctional transmembrane proteins mediate cell adhesion by homophilic interactions and form a zipper-like structure along the cell border. This adhesion is reorganized during monocyte transendothelial migration (79). Indeed, tight and adherens junctional proteins play a critical role in this process ( Table 2 ) (24). Tight junctions are localized at the apical site of the interendothelial junctions and form a close contact between adjacent ECs. Tight junctions are composed of occludins, claudins and junctional adhesion molecules (JAMs), but only JAMs have been described to participate directly in the transendothelial migration of monocytes (80). Three members of the JAM family have been described: JAM-A, JAM-B, and JAM-C. JAMs from ECs bind to monocyte integrins. LFA1 has been identified as a ligand for JAM-A (57). JAM-B has been described to bind to α4β1-integrin and JAM-C to αMβ2-integrin (also known as MAC1 and CD11b– CD18) and αXβ2-integrin (also known as CD11c–CD18) (58, 59). Moreover, JAM-C is specifically required to prevent reverse transmigration of monocytes back to the vascular lumen (81). The interaction between the members of the JAM family and the integrins expressed by monocytes allows the transmigration through tight junctions ( Figure 1 ). Then, monocytes transmigrate through the adherens junctions. The main component of adherens junctions is the vascular endothelial cadherin (VE-Cadherin), an endothelial-specific protein anchored to the cytoskeleton and responsible for endothelial tightness against leakage (24). VE-cadherin plays an important role on the control of vascular permeability and integrity but does not interact with monocyte proteins to facilitate transmigration. In contrast, molecules present in adherens junctions such as platelet/endothelial cell-adhesion molecule 1 (PECAM1) and CD99 participate in this process by homophilic interactions (24, 60, 61) ( Figure 1 ). VE-cadherin is crucial to regulate endothelial permeability because it participates in adherens junctions dismantling of and EC retraction, which is required to complete the transmigration of monocytes (60). The clustering of selectins and/or VCAM/ICAM induces an activation of RhoA and an increase in intracellular free calcium within the endothelial cells (82). This results in the activation of the calmodulin-dependent enzyme myosin light chain kinase (MLCK), thereby causing a conformational change in myosin II (83) and the phosphorylation of the VE-cadherin cytoplasmic tail (82). ICAM-1 engagement also results in the activation of Src and PYK2 kinases, which also phosphorylate VE-Cadherin (84). The phosphorylation on Tyr658 and Tyr731 induce the dissociation of VE-cadherin from the cytoskeleton and allow the splitting of EC junctions (82). These changes lead to the increase in vascular permeability and allow monocyte extravasation (60). Monocytes mostly transmigrate through junctions between adjacent ECs (paracellular transmigration) although monocytes can also migrate through ECs (transcellular transmigration) by the formation of vesiculo-vacuolar organelles (85).

The reorganization of interendothelial junctions during inflammation is temporally and spatially regulated by inflammatory mediators and leukocyte transendothelial migration (86). These changes are reversible, and endothelium quiescence and vascular permeability are restored once the triggering cause is removed. However, in some pathological conditions such as chronic inflammation and atherosclerosis, the ECs remain activated and the interendothelial junctions become instable (87). This instability causes an impairment in the endothelial barrier function leading to uncontrolled leukocyte migration and vascular leakage. Defects in the organization of endothelial cell junctions can lead to vascular malformations, vascular fragility and rupture, and appearance of hemorrhages and edema (88). Loss of barrier integrity is a common feature in several vascular disorders including anaphylaxis, diabetic microangiopathy, angioedema, or cancer and metastasis (85). Endothelial junctions not only mediate adhesion but also trigger intracellular signals that communicate cell position, limit growth and apoptosis. They are essential to maintain vascular integrity and homeostasis (88). Furthermore, the reorganization of interendothelial junctions and loosening of cell-cell adhesion is also required for other physiological processes such as angiogenesis (85).

Vascular sprouting or angiogenesis is one, but not the only, process of blood vessel formation in the adult. Ordered angiogenesis has long been considered a critical mechanism for optimal wound healing. Little is known about the molecular basis by which leading ECs at vascular sprouts (endothelial ‘‘tip’’ cells) are designated to grow and elongate to form new blood vessels. Some investigations show that direct interactions of monocytes with ECs may be a driving force to stimulate endothelial proliferation (93, 94) and to mediate the fusion of endothelial tip cells (95). Indeed, some investigators have demonstrated that circulating monocytes are selectively recruited to certain regions of regenerating livers after hepatectomy ( Figure 2A ), particularly surrounding sprouting points (91) ( Figure 2B ).

Monocyte recruitment initiates in portal areas and expands to the rest of hepatic tissue in correlation with vasodilation and the expression of the inducible form of nitric oxide synthase (iNOS). iNOS is upregulated in injury and induces the synthesis of the vasodilator and proangiogenic substance NO (96). Indeed, angiogenesis initiates with vasodilation, a process involving NO (89). Then, vascular permeability increases in response to proangiogenic factors such as VEGF, plasma proteins extravasate and pave the ground with a provisional path for the migration of ECs. In this scenario, vascular permeability is affected by the formation of fenestrations, vesiculo–vacuolar organelles and the relocation of PECAM-1 and VE–cadherin, which implicates Src kinases (97, 98). Although angiogenesis requires increased permeability, vascular leakage, and release of permeability factors such as VEGF, it needs to be finely regulated to avoid water and sodium imbalance, circulatory collapse, intracranial hypertension, or ascites (18) among other pathological conditions. Either VEGF or other proangiogenic factors such as angiopoietins may be released by monocytes and MDM to regulate vascular permeability (92, 99). Angiopoietin 1 (Ang-1), a ligand of the endothelial Tie2 receptor, is an endogenous inhibitor of vascular permeability via strengthening of endothelial junctions (100). In contrast, angiopoietin 2 (Ang-2) is a partial agonist/antagonist of Tie2, thus promoting vascular leakage (101, 102). Indeed, Ang-2 is involved in the processes of detachment of smooth muscle cells and loosening of the ECM (103). In addition, MDM release different matrix metalloproteinases (MMP) that may activate or liberate a myriad of growth factors (bFGF, VEGF, IGF-1, etc) retained within the extracellular matrix (104, 105).

Substances released by parenchymal cells (damage-associated molecular patterns) and resident macrophages (e.g. TNF-α) during tissue injury serve not only to coordinate vessel and tissue growth, but also cellular interactions, attracting circulating monocytes (e.g. MCP-1) and inducing neighboring ECs to expose monocyte adhesion molecules such as those described in the section 2.2 of this review (106) ( Figure 3 ).

Circulating monocytes detect attracting signals and interact with ECs to initiate endothelial disruption and monocyte translocation to local sprouting points. It has been demonstrated that the number of interactions of recruited monocytes with liver vascular network during regeneration is directly associated with phosphorylation and disruption of VE-cadherin connections (91). This uncoupling of inter-EC connectivity mediated by VE-cadherin is critical to the plasticity of the selected endothelial tip cell and for EC migration and elongation (107). MDM also serve as chaperones of endothelial sprouting by locally secreting proliferative factors, such as Wnt5a and Ang-1 and the stalk cell stabilizer Notch1 ( Figure 4 ).

The release of Wnts from infiltrating monocytes and, namely, the contribution of Wnt5a and non-canonical ligands is especially important to harmonize angiogenesis in inflamed vessels (108).. Recruited monocytes are important beyond the priming phase of angiogenesis and throughout the process of tissue regeneration. Indeed, leukocyte adhesion molecules such as P-selectin, CCR2, and VCAM-1 upregulate during tissue regeneration and maintain the number of rolling interactions and the likelihood of recruiting monocytes. Specifically, the adhesion molecule ICAM-1 is upregulated after hepatectomy, but its gene expression is significantly downregulated when monocyte interactions and VE-cadherin phosphorylation are maxima. This points to a precise regulation of this adhesion molecule by monocyte interactions in accordance with the requirements of endothelial sprouting and the subsequent hepatic mass expansion. In fact, ICAM-1 activation is an important signaling pathway to trigger vascular sprouting (109, 110) and arteriogenesis (111). ICAM-1 is then an excellent candidate to understand the role of direct interactions of monocytes with endothelium to regulate vascular and tissue regeneration. Indeed, gene suppression of any of the subunits of the monocyte receptor Mac-1 (CD11b/CD18) disrupts wound healing in mice (112, 113). Moreover, suppression of the CD11b gene drops survival in mice undergoing partial hepatectomy and hinders vascular and liver mass regeneration in line with a reduced infiltration of circulating monocytes into the hepatic vascular network (91). Interestingly, the lack of CD11b also induces TNF-α expression, which can also directly promote VE-cadherin phosphorylation to replace the missing effects of monocyte-endothelial cell interactions (114). However, this increase in TNF- α is followed by an intense vascular leakage and a disorganized and aberrant vascular network after hepatectomy (91). Indeed, exacerbated increase of TNF-α by monocytes or MDM is associated to suppressive effects on wound healing in mice (115). To regulate these vascular disorders, tissue macrophages, such as KC, may progressively move into vessel walls from their static state and location in an attempt to replace the role of monocyte-EC interactions in the control of vascular and tissue growth in ICAM-1 KO mice (91). Thus, macrophage interaction with ICAM-1 in endothelium seems a critical step in the regulation of the endothelium integrity and in the control of TNF-α expression during angiogenesis after hepatectomy.

The molecular basis of vasculogenesis (in the embryo and from endothelial progenitors) diverges from that of pathological angiogenesis in the adult. The formation of the vascular network in the embryonic phase requires several sequential steps combining both mechanisms, vasculogenesis and angiogenesis. Vasculogenesis gives rise to the heart and the initial embryonic vascular plexus and surrounding membranes comprising the yolk sac circulation (116). Angiogenesis accounts for the expansion and remodeling of this vascular tree via endothelial sprouting and intussusceptive microvascular growth. However, little is known of any possible direct implication of monocyte or macrophage-EC interactions to drive vasculogenesis. The fact is that the macrophage is one of the first blood cell lineages to originate during embryonic development. Macrophages generate and grow surrounded by ECs and vasculogenesis occurs in parallel with hematopoiesis (116). Studies in mice have revealed that embryonic macrophages arise during three different waves of hematopoiesis: primitive hematopoiesis, erythro-myeloid progenitor (EMP) generation, and definitive hematopoietic stem cell-mediated hematopoiesis (116). Macrophages are then distributed through most developing organs (117). These initial macrophages derived during primitive hematopoiesis behave as a mediator between neovascularization and organ architecture during fetal organogenesis (118). Further recent findings using inducible Csf1r promoter-driven-Cre ROSAYFP reporter mice support a direct relationship between blood and endothelial lineages (119). These authors found that circulating EMP contribute to ECs in vascular network in multiple tissues (liver, brain, heart, lung, and yolk sac), and their interaction continues throughout adulthood (119). Other authors have found evidence on the active role of macrophages to promote vasculogenesis during retinal neovascularization (120). They have shown that macrophages boost the recruitment and differentiation of bone marrow-derived cells (BMCs). Mechanistically, they found that specifically M2-like macrophages affected the migration and activation of BMCs via secretion of VEGF and stromal cell-derived factor-1 (SDF-1). This is consistent with another investigation that demonstrated a higher recruitment of BMCs by SDF-1 and hepatocyte growth factor (HGF), released by the interaction between macrophages and matrix-embedded endothelial cells (MEECs) during liver regeneration (121). Namely, HGF stimulated the expression of the receptors CXCR4 and CXCR7 (122), that promoted the mobilization of endothelial progenitors to the blood stream and their recruitment into injured liver. In turn, incorporated endothelial progenitors secreted more HGF promoting positive feedback and the formation of new blood vessels that irrigated the implants and the ischemic tissue (121).

Vascular development is one of the earliest organogenesis events in embryonic development. A primitive vascular tree provides a basic path for circulating cells and guarantees the supply of nutrients. EC differentiation arises during gastrulation when cells invaginate to form the mesoderm. This process occurs around the embryonic day E7.25 in different clusters of cells in the extra-embryonic yolk sac, called blood islands (123). Blood islands are disposed of primitive hematopoietic cells in the center and aligned endothelial cells in the periphery (124). Primitive hematopoiesis produces unipotent myeloid progenitors that may uniquely generate the macrophage lineage (124), bipotent progenitors of erythrocytes, and megakaryocytes (125). Then, these progenitors are mobilized to the blood circulation around E8.0 (124). The first embryonic-derived macrophages are detected in the yolk sac at E9.0 (126). Yolk sac-derived macrophages colonize first the developing brain by E9.5 and then the rest of the embryonic tissues by E12.5 (123, 124). Although primitive macrophages are generated directly from progenitors without going through a monocyte intermediate (126), it remains elusive the possible interplay with endothelium during this phase to understand positioning and growth of the fetal vascular tree during organogenesis. Both vasculogenesis and macrophage generation occur in parallel in space and time, but how direct interactions of nascent macrophages or monocytes with ECs contribute to vasculogenesis need further investigation.

Infiltration of circulating monocytes to the tumor microenvironment (TME) is critical for tumor angiogenesis (127). It is well-known that inflammation is a starting event to attract and recruit monocytes and a driving force for monocyte-endothelial cell interactions and extravasation. For this reason, cancer cells use these endogenous mechanisms to stimulate an inflammatory milieu and release angiogenic factors that stimulate the endothelium to expose adhesion molecules, which enable adhesion and extravasation of proangiogenic monocytes (128). There are different markers described for these proangiogenic monocytes that cancer cells recruit to the TME. Different authors have found that human CD16⁺ patrolling monocytes promote angiogenesis and boost the expansion of human colorectal carcinoma xenografts (128, 129). These CD16⁺ monocytes seem to be recruited to the TME by cancer-released inflammatory cytokines and angiogenic factors (TNF-α, IL-1β, IL13, VEGF, etc.). In contrast, other investigations have described that inflammatory GR1⁺ monocytes are the proangiogenic monocyte subset that supports the growth of primary tumors (130, 131). In any case, once proangiogenic monocytes are attached to inflamed endothelium within the TME, these monocytes are locally retained by endothelial CX3CL1/Fractalkine released by ECs in response to interferon gamma (IFN-γ), which is present in the inflammatory locus (132). CX3CL1 is a distinctive CX3C chemokine that is anchored to the cell membrane to allow leucocyte adhesion (133, 134), although it is also present in a soluble form that exhibits monocyte and lymphocyte chemotaxis properties (135). Furthermore, CX3CL1 also facilitates vascular extravasation of monocytes in lung tumor metastasis (136).

Hypoxia is a driving force of angiogenesis in tumors (137, 138). Some investigations have described that hypoxia, via hypoxia-inducible factor-1 (HIF-1), enhances the expression of proangiogenic factors such as VEGF, Ang-1 and Ang-2 in endothelial and cancer cells (139, 140), and promotes the synthesis of CXCR4 (a receptor for CXCL12) and Tie2 (angiopoietin receptor) on macrophages, which allows the interstitial migration of proangiogenic macrophages inside the tumor (128, 141, 142). Numerous tumor-derived chemokines are critical for recruiting monocytes into the tumor milieu and to promote the transition of monocytes to tumor-associated macrophages (TAM). These include chemokines such as CCL3 (macrophage inflammatory protein, MIP1α), CCL2 (MCP-1) and CCL4 (MIP1β), interleukins (IL-6 and IL-1β) and cytokines (colony stimulating factor 1 (CSF-1) (143–145). Monocytes recruited into the tumor are then further reprogrammed by cancer cells to display a proangiogenic and immunotolerant M2-like macrophage phenotype (146). Indeed, tumor-associated macrophages (TAMs) are the most abundant immunosuppressive cells in the TME. They play a fundamental role in the tumor initiation, growth, and progression (147). M2-like TAM, under hypoxic milieu, also release proangiogenic factors such as VEGF and placental growth factor (PIGF), and chemokines such as CCL2 and CXCL9, that regulate the expansion of peritumoral vascular network (143, 145). Additionally, TAMs are also involved in immunosuppression of CD8⁺ T cells and natural killer (NK) cells, a major mechanism of anti-tumor immunity (148, 149).

The proangiogenic activity of TAM is also mediated by MMP activity, which contribute to the release of matrix-bound growth factors such as VEGF. For example, active MMP-9 is produced by mouse and human proangiogenic Tie2⁺ monocytes (150). The release of different matrix-bound growth factors from TME by active MMP-9 represents one of the most challenging mechanisms for current therapies to interfere with tumor angiogenesis (141). Indeed, digestion and delivery of angiogenic factors by MMPs is a vicious circle for tumor angiogenesis. Tumor tissues synthetize and accumulate MMPs and growth factors in the extracellular matrix, and simultaneously induce the arrival of more proangiogenic monocytes. Then, these monocytes infiltrate and transdifferentiate into TAM and secrete additional MMP-9 and growth factors to the TME, as suggested by previous studies in mice (151, 152).

Hypoxic TAMs show deep variations in the expression of numerous metabolic genes because they are compelled to adjust their metabolism to low oxygen pressure to maintain the energy needs (153). Cytokines are also important effectors on macrophage metabolism, inducing a wide array of metabolic changes. For example, pro-inflammatory M1-like macrophages change their metabolism toward increased anaerobic glycolysis, pentose phosphate pathway activation, and protein and fatty acid synthesis (154). In contrast, cytokines such as IL-4, IL-10, and IL-13 released by M2-like macrophages lead to a phenotype that more closely resembles the characteristics of TAMs (displaying enriched oxidative phosphorylation and stable glycolysis) (155). It is known that metabolic changes influence angiogenic and immunosuppressive properties of hypoxic TAMs. One signaling pathways governing these events is REDD1, a negative regulator of mTOR (156). Indeed, REDD1-mediated inhibition of mTOR hampers glycolysis in TAMs and reduces their excessive angiogenic response promoting the formation of anomalous blood vessels. Hence, TAMs lacking REDD1 promote the formation of smoothly aligned, pericyte-covered, functional vessels preventing vascular leakage, hypoxia, and metastases. TAMs deficient in REDD1 are highly glycolytic and drain glucose from TME affecting nearby ECs. This hinders vascular hyperactivation and stimulates the formation of quiescent vascular junctions (156). This functional link between TAM metabolism and tumor angiogenesis could be exploited in the future for the design of novel anti-angiogenic therapies for cancer.