Monocytes and macrophages largely contribute to the pathophysiology of cardiovascular diseases, for example, in atherosclerosis [
4,
37,
57,
62,
120,
164] and arteriogenesis [
55,
58]. Both monocytes and macrophages can, at the extremes, be divided in a proinflammatory phenotype and a healing phenotype. The interplay and balance between these two phenotypes have shown to be of importance in, for example, atherosclerosis [
25,
29,
130] and myocardial infarction [
37,
154]. In murine monocytes, the proinflammatory phenotype is defined as Ly6C high, while the healing phenotype is defined as Ly6C low [
159]. Ly6C high monocytosis is regarded as one of the first steps in the inflammatory response in atherosclerosis, as Ly6C high monocytes activate endothelium, infiltrate into the intima, and become lesional macrophages. Furthermore, in atherosclerosis models, such as the apolipoprotein (ApoE) deficient mouse, hypercholesterolemia is associated with Ly6C high monocytosis. Inhibition of the Ly6C high monocytosis abolishes atherosclerosis in hypercholesterolemic mice [
26,
87,
136]. In humans proinflammatory, or classical, monocytes are generally defined as CD14++/CD16−, while the healing, or non-classical, phenotype is defined as CD14+/CD16++ [
166]. An intermediate, CD14++/CD16+ population can also be observed in humans [
99,
153]. In concurrence with the animal model described above, in humans, CD14++/CD16− monocytosis is associated with atherosclerosis and is an independent predictor of cardiovascular events [
61,
123]. In macrophages, the phenotypic spectrum is defined by the proinflammatory M1 macrophages that are induced by T-helper 1 cytokines, and by M2 macrophages that are induced by Th-2 cytokines. The M2 macrophages can be subclassified into wound healing (M2a), regulatory (M2b, M2c), and M2d subtypes [
24,
25,
104]. In addition, atherosclerosis-associated macrophage phenotypes have been discovered, i.e., M(Hb), Mox, Mhem, and M4 macrophages [
24,
25]. Consequently, a large number of macrophage phenotypic markers have evokes (reviewed by Mosser et al. [
104]. and Colin et al. [
25]). While CD40 is not mentioned in these reviews, it has proved to be a distinctive marker for M1 macrophages [
148,
149]. In experimental atherosclerosis models, the M1 and the plaque specific M4 subtypes are proinflammatory and proatherogenic and seem to cause a vulnerable plaque phenotype. The M2 phenotype and the plaque specific M(hb) and Mhem are anti-inflammatory and antiatherogenic. The role of the Mox phenotype is currently not well understood [
25,
29]. The role of the M2 subtypes has not been defined further yet. In arteriogenesis in animal models, the shift toward M2 phenotype (no data on subtypes) improves arteriogenesis and reduces ischemia [
51,
138,
140]. In humans, M1 macrophages are associated with plaque instability, both in ischemic stroke and in myocardial infarction [
23,
81,
134]. A word of caution should be added, regarding the dichotomous distinction between M1 and M2 macrophages, as these terms are increasingly discouraged by immunologists. In vivo, a wide range of M1- and M2-like macrophages can be distinguished. While older studies use the M1/M2 nomenclature, it is now encouraged to use multiple markers to describe the macrophage phenotype [
47]. However, this review will still use the M1/M2 nomenclature, as the studies described all use this nomenclature.