Earlier studies suggested that EPCs are a group of cells mobilized from bone marrow that participate in endothelium repair after injury (35). In fact, EPCs have a variety of tissue sources, including bone marrow, spleen, blood vessel wall, lipid, and placenta (12). At present, EPCs are defined as the cell population that has the typical clonal proliferation ability and characteristics of stem cells and can differentiate into mature ECs (36).

EPCs actually consist of different cell populations, making up “early EPCs” and “late EPCs” (10). The early stage EPCs appears in early culture stage (4–7 days), its survival time is short and will not differentiate into ECs. EPCs can activate adjacent cells by releasing SDF-1 and VEGF to promote vascular growth (37). It's classical immunophenotypes are CD45⁺,CD14⁺, and CD31⁺ and CD146⁻,CD133⁻, and Tie2⁻ (10). The late stage EPCs can be known as endothelial colony-forming cells (ECFCs), derived from blood vessel wall, human placenta, and white adipose tissue (38). Compared with the early stage EPCs, ECFCs has a higher degree of proliferation and longer survival time, and can differentiate into mature functional ECs to participate in vascular repair (39). It's typical immunophenotypes are CD31⁺, vWF⁺, VE-cadherin⁺, CD146⁺, VEGFR2⁺, and CD45⁻, CD14⁻.

By studying HUVECs and HAECs, it was found that the renewal of vascular wall ECs could be attributed to ECFCs (40). EPCs residing in blood vessels possess multiple abilities such as self-renewal, multi-differentiation potential, and robust proliferation (16). The research pointed out the vital role of Sox18/SoxF transcription factor in the differentiation process. The resident CD157⁺EPCs in vascular wall of large arteries and veins showed regenerative potential of endothelial cells and vasculature (41). Animal studies have proved that EPCs can reduce the formation of neointima after artery injury and restore endothelial function (2). EPCs homing play a central role in vascular remodeling (42). Then neurotrophic factor-3 (NT-3) was proved to be able to accelerate rapid re-endothelialization of damaged carotid arteries by promoting EPCs mobilization and homing (42). It is also regulated by angiogenic chemokines (CXCL1, CXCL7, CXCL12, and CCL2), through their corresponding receptors (CXCR2, CXCR4, and CCR2) (43).

One of the characteristics of SMPCs is the heterogeneity of their origin (44). It is believed that the regenerative VSMCs after vascular injury have several different sources (28). The main functions are contracting blood vessels, regulating angiotasis, and blood pressure (45). There are different sources of VSMCs in different segments of the aorta, expressing different molecular markers and having different functions (2).

Studies have found that if blood vessels are injured, VSMCs will migrate to the intima, changing from a higher differentiated contractile phenotype to a secretory one to initiate cell proliferation (46). It is characterized by increased proliferation, migration, ECM synthesis, along with decreased expression of contraction markers (47). The traditional view holds that imbalance of VSMC plasticity leads to maladaptive phenotypic transformation which leads to the progression of VSMC-driving vascular remodeling diseases (48). But now we found that in vascular injury and repair, sometimes only contractile VSMCs are involved in vascular remodeling process without dedifferentiating to a secretory phenotype (4). Other studies have demonstrated that VSMCs can participate in vascular remodeling process without phenotypic transition (4, 49). From the perspective of stem cell research, recent results have confirmed that VSMCs derived from VSCs can drive vascular remodeling and take part in vascular repair upon injury.

In 2004, Hu et al. (7) first confirmed the presence of Sca-1⁺, c-Kit⁺, CD34⁺, and Flk1⁺ progenitors in the aortic root of Apoe^−/− mice (36). They found that Sca-1⁺ resident adventitial progenitor cells can migrate and differentiate into VSMCs, playing an important role in atherosclerosis. Later, another group also reported that Sca-1⁺, CD34⁺, and PDGFRβ⁺ cells residented in the adventitia can differentiate into VSMCs in vitro. They also reporterd that the process is mediated by acoustic hedgehog (Shh) signaling pathway (50). Shh signaling is limited to the adventitia of the artery and may play a part in the maintenance of VPCs mainly in adventitia (50). Peripheral vascular cells (VSMC and pericytes) may share a common FlK1⁺ progenitor cell with ECs. FlK1 is a key regulator of phenotypic transformation in VSMC which inhibits VSMC differentiation and maintains the Sca-1⁺ progenitor cell phenotype, facilitating multidirectional differentiation and preventing pathological vascular remodeling (47). Based on lineage tracing study, Gli1⁺ cells were also proved to be progenitor cells in the adventitia, expressing CD34, Sca-1, and PDGFRβ and contributing to vascular repair and related diseases (51).

MSCs are pluripotent stromal cells which have proliferative and immunomodulatory effects (52). MSCs from different tissues share the same triadic differentiation potential, that is, the ability to differentiate into osteoblasts, chondrocytes, and adipocytes. The cells both express typical markers CD13, CD73, and CD90 in intima as well as CD29, CD44, and CD105 in adventitia and intima. However, the differentiation tendency of MSCs from different sources also differ (53). Bone marrow-derived MSCs express SH2, SH3, CD29, CD44, CD71, CD90, CD106, CD120a, CD124, and easily differentiate into osteoblasts. Adipose-derived MSCs express CD34, CD13, CD45, CD14, CD144, CD31, and easily differentiate into adipocytes (14, 54). Studies found that adipose tissue stem cells are easier to isolate and more abundant compared with other types of MSCs, they can sidestep ethical issues so are widely used in stem cell studies (55).

Some research groups (56) have isolated a population of CD34⁺CD31⁻ cells expressing pericyte and mesenchymal antigens showing high proliferation and multiple-directional differentiation ability. It can have bidirectional interaction with ECs and take part in angiogenesis. It has been proved that co-culture with ECs on electrostatic spinning scaffolds can promote the differentiation of MSCs into osteoblasts (57). In the mouse model of hind limb ischemia, the researchers also found that EC-like cells derived from MSCs perform strong angiogenesis ability in vitro (58). Bone marrow mesenchymal stem cells (BMMSCs) can differentiate into ECs and VSMCs in vitro by means of growth factors modulation (59). MSCs are present in the perivascular niche of many organs, including kidneys, lungs, liver, and heart. The vascular-resident Gli1⁺ MSCs are the main cellular source of injury-induced organ fibrosis attributed to their colony-forming activity and differentiation capacity into fibroblasts (60). The effects of these cells in vascular repair depend on their metabolic reprogramming and SMC differentiation ability via mir-378a-3p/TGF-β1 signaling pathway (61).

Pericytes are high density parietal cells located in terminal arterioles and capillaries (62, 63). Pericytes are characterized by direct contact with the underlying ECs. It can regulate capillary permeability, endothelial stability, and micro-vasoconstriction (64). In fact, there are still no specific molecular markers for pericytes. The pericyte markers currently known, such as NG2, CD146, PDGFR-B in media and adventitia, are also expressed in SMPCs and MSCs (64).

In 1992, pericyte was first reported for its osteogenic potential, it has been shown that pericytes reside in capillary and microvessels may be osteoblast progenitors (65, 66). Pericytes and MSCs derived from various human tissues are similar in their function of maintenance vascular homeostasis. Pericytes can help maintain tissue homeostasis by promoting local MSC proliferation and differentiation through the paracrine capability (67). In a systematic investigation, the researchers found the angiogenesis and multilineage differentiation potential of pericytes and MSCs from different human tissues in vitro, and enriched CD34⁻CD146⁺ pericytes in adipocytes and bone marrow by magnetic activated cell sorting (15). Only bone marrow-derived cells showed triadic differentiation potential, while adipocyte-derived cells exhibited poor chondrogenic differentiation under TGF-β1 stimulation. These results indicate that the regenerative potential of pericytes as stem cells depends on their tissue origins (15). Recent lineage tracing experiments using the induced Tbx18-CreERT2 cell line showed that pericytes maintained the identity under various pathological conditions such as vascular senescence and will not differentiate into other cells. This discovery challenged the view of pericytes as stem cells (68).

Atherosclerosis is characterized by endothelial damage, VSMC proliferation, and collagen deposition, as well as local thickening of the arterial wall caused by lipid deposition (78). Blood flow in vulnerable areas such as arterial branches has a high oscillation index and a low shear stress (79). This fluid mechanical force can directly act on ECs changing cell morphology, cytoskeleton and intercellular conjunctions, and increasing oxidative stress (80). Low density lipoprotein causes cholesterol storage when attached to the intima of the artery (81). Monocytes enter the intima from the blood, adhere to ECs and turn into macrophage. After phagocytic and ingestion of cholesterol, they form “foam cells” resulting in necrotic nuclei of atherosclerotic plaques with VSMCs (82). Fibrous cap inflammation can determine plaque stability (81). The death of VSMCs, degradation of collagen, and ECM lead to thinning of the vascular cap, resulting in increased plaque rupture with serious consequences. In fact, lumen stenosis often results from repeated ruptures and repair of complex plaques (83).

Essential hypertension is defined as an unexplained increase in blood pressure that increases the risk of cardiac, brain, or kidney events. Essential hypertension is often associated with hypercholesterolemia, obesity, and diabetes. These risk factors are also present in cardiovascular disease and hypertension can worsen the symptoms (105).The pathogenesis of hypertension includes endothelial dysfunction, sympathetic nervous system activation, inflammation, oxidative stress, etc. Aldosterone can promote the polarization of macrophages to the pro-inflammatory M1 phenotype, leading to vascular dysfunction and aggravating hypertension (106). In hypertension, collagen deposition is the main factor resulting in vascular fibrosis (107). VPCs participate in the occurrence and development of hypertension and vascular fibrosis is related to a variety of signaling pathways.

In the aorta of hypertensive mice induced by Ang II, the number of Sca-1 + progenitor cells increased and the EGFP-Sca-1⁺ progenitor cells co-located with the deposition areas of collagen I, III, and V in the adventitia, suggesting that Sca-1⁺ progenitor cells may be the source of hypertensive vascular fibrosis (76). Lineage tracing technique displayed Adv-Sca-1 cells can differentiate into fibroblasts in the case of vascular injury, leading to vascular remodeling and sclerosis, while KLF4 may maintain the phenotype and prevent pathological vascular remodeling (13). SMPCs express PW1 in the adventitia and participate in pulmonary hypertension-related vascular remodeling (20). The number of PW1⁺ progenitor cells increased significantly in the mouse pulmonary hypertension model under hypoxia and were able to differentiate into VSMCs through the CXCR4 pathway (20). Dysfunctional ECs can induce FoxM1 expression in VSMCs and activate FoxM1-dependent VSMC proliferation, confirming ECs and VSMCs interaction through FoxM1 signaling in vascular remodeling and promoting hypertension and fibrosis (74). Recently, a study induced perivascular fibrosis through Ang II, and found that vascular remodeling during the process was not dependent on blood pressure regulation but through ADAM17 activating PDGFR then acting on ECs (108). ADAM17 may be a new clinical target for preventing hypertension complications (109).

Aortic aneurysm refers to local dilation of the aortic lumen ≥50% of its original diameter and structural degeneration of different segments of the aorta. Endothelial injury, VSMCs loss and ECM degradation lead to abnormal remodeling of the aortic wall resulting in aortic aneurysm and separation of layers of the aortic wall (aortic dissection) (110, 111). The composition and integrity of ECM are key determinants of the physical properties of the aortic wall (112). ECM undergoes continuous physiological remodeling and the original proteins degraded and replaced by the newly synthesized proteins. MMP plays an important role in this process. Therefore, MMPs are closely related to the pathogenesis of aortic aneurysm (113). Aortic aneurysms can progress gradually, leading to tears in the intima of the aorta or bleeding in the wall of the aorta, further leading to the formation of aortic dissection, which can be life threatening.

Aortic aneurysm formed in two main sites, thoracic aorta and abdominal aorta (114). Abdominal aortic aneurysm (AAA) is most associated with atherosclerosis, they share many common risk factors. Thoracic aortic aneurysms (TAA), located in the aortic root and ascending aorta, are more related with genetic syndromes such as Marfan syndrome (115). AAAs are marked by media and elastic fiber degradation, leading to aortic dissection (116). The pathogenesis of AAA includes VSMCs apoptosis, MMPs degradation of elastin, collagen and glycosaminoglycan, inflammatory reactions and the role of reactive oxygen species (117). Among them, apoptosis of VSMCs and degeneration of aortic media are the hallmark pathological changes of AAA. Studies have found that Il-18 receptor defect, chemokine netrin-1 deficiency, and activated transcription factor EB can reduce apoptosis of VSMCs, decrease the activity of MMP-2/9 and elastin degradation, inhibiting the occurrence and progression of AAA (118). The pathogenesis of TAA includes changes of ECM, apoptosis of VSMCs, MMPs and reactive oxygen species. Mutations of TGFBR1, TGFBR2, SMAD3, TGFB2, COL3A1, FBN1, and other genes can cause the occurrence of TAAs (119). For example, firillin-1 is the major subunit of microfibers that constitute the ECM of the thoracic aortic wall. Changes in Firillin-1 result in reduced adhesion between elastic fibers and VSMCs, thereby damaging the biomechanical integrity of the aortic wall and ultimately leading to Marfan syndrome (120). Fibrllin-1 is highly homologous to potential TGFβ binding proteins, and TGFβ gene defects are found not only in Marfan syndrome but also in Patients with Loeys-Dietz aortic aneurysm syndrome (121). A recent discovery found MFAP4 glycosylation was enhanced in MFS patients, and its expression was further enhanced in the advanced aneurysm stage (122). They also induced pluripotent stem cells to differentiate into VSMC in MFS patients and found that there was no elastin expression and the expression level of MFAP4 was unchanged.

VSMC reprogramming to a MSC-like state may play a key role in the progression of AAAs (123). During the pathogenesis of AAA, the TGF-β signaling pathway of VSMCs was inhibited. The decreased expression of TGF-βR2 could lead to reduced binding of Smad2/3 to transcription factor KLF4, leading the transformation of contractile VSMCs into MSCs-like cells. MSCs possess high plasticity and potential to differentiate into several different cell types, such as osteoblasts, chondrocytes, adipocytes, and macrophages. This characteristic has implications for aortic dilation, aortic dilation, calcification of the aortic wall, and inflammation, thereby promoting the development of aneurysms (123). Another research found Smad3 gene mutations in the second cardiogenic SMPCs and neural crest SMPCs prevented their differentiation into VSMCs and reduced the level of proelastase. This suggests that CPC-SMPCs and NCSC-SMPCs can differentiate into VSMCs through the SMAD3-dependent TGF-β signaling pathway (124). ECs differentiation was reduced in patients with AAAs compared with healthy human MSCs, confirming that the aging MSCs impaired its original vascular repair ability, initiating the occurrence and progress of AAAs (125). Some studies have confirmed that MSCs from calcified and inflammatory aorta have high osteogenic potential and pathological angiogenesis ability under appropriate stimulation (126). Runx2 can enhance the proliferation of MSCs and induce them differentiate into osteoblast lineage cells by regulating Shh, Fgfr2/3, Wnt, and Pthlh signaling pathways (55). Runx2-mediated micro-calcification is a new pathological feature of AAA. It may be a promising strategy for clinical improvement of disease treatment regimens (127). Resident NG2⁺ progenitor cells can differentiate into VSMCs after aortic injury during aortic aneurysm and dissection, producing growth factors that promote endothelial survival and vascular repair (77) (Figure 3).