Review Article

Are Endothelial Progenitor Cells the Real Solution for Cardiovascular Diseases? Focus on Controversies and Perspectives

Table 2

Key players involved in modulating circulating EPC levels and functions.

FactorsEffectsReferences

Factors and conditions associated with altered circulating EPCs levels
Aging It determines a decrease in progenitor cells activity and mobilization [26, 27]
Inflammation Restricted acute inflammatory response stimulates EPCs mobilization while persistent chronic inflammatory stimuli have deleterious effects and result in decreased number of circulating mature and functional EPCs
C-reactive protein (CRP) exerts direct inhibitory effects on EPC differentiation and survival. Proinflammatory TNF-α reduces EPCs number
[28, 29]
Oxidative stressIt reduces EPCs number, induces apoptosis, and reduces EPCs capacity of mobilization, migrating, and incorporating into vasculature [28, 29]
Hypothyroidism It decreases CD34+/CD133+/KDR+ EPCs [31, 32]
Cardiovascular risk factors (smoking, diabetes, hypertension, lipid disorders, abdominal obesity, metabolic syndrome, etc.)They influence the circulating levels of EPCs; precisely they reduce their levels [30]
HyperparathyroidismIt increases circulating EPCs levels[31, 32]

Physiological factors involved in EPCs mobilization
GenderIt upregulates VEGF and SDF-1
It modulates EPCs levels and cardiovascular risk profile, due to the beneficial effects of estrogens particularly in women
The increase seems to be related to oestrogens levels
[33]
PregnancyIt increases EPCs-derived colonies [34]

Drug therapies modulating circulating EPCs levels
Antihypertensive drugs[35]
 Calcium channel blockers (CCBs) nifedipine and barnidipineThey enhance EPC number and function
 Angiotensin II receptor blocker (ARB) telmisartanIt enhances EPC number and function
 Angiotensin converting enzyme (ACE) inhibitorsThey improves clonogenic capacity [35]
Cholesterol lowering medications
 Statines (atorvastatin, rosuvastatin)They increase mobilization of EPCs and CD34+/CD117+, CD34+/CXCR4+[35]
Antidiabetic medications
 Oral dipeptidyl peptidase-4 inhibitor (sitagliptin) It increases number of circulating EPCs in patients with diabetes [35]
 Thiazolidinedione/metforminThey improve EPCs number and function
Other drugs
 EstradiolIt improves capacity of neovascularization [26]
 PPAR-γ agonistIt increases EPCs migration [26]
 CXCR4 agonists They stimulate SC mobilization [26]
 AMD3100 (plerixafor)It increases CD34+, CD117+, and CD133+ cells
 POL6326
 ErythropoietinIt increases EPC and HSC levels[24]
 Nitroglycerin (chronic use)It increases apoptosis and decreases phenotypic differentiation and migration[26]
 Granulocytes colony stimulating factor (G-CSF)It induces SC mobilization by interruption of CXCR4/CXCL12, c-Kit/SCF, and VLA-4/VCAM-1 axis [26]
 Growth hormoneIt reduces apoptosis [26]
It improves EPCs migratory capacity

Lifestyle modification and nutritional interventions
Red wine resveratrol, salvianolic acids, Gingko Biloba, ginsenoside, berberine, and puerarine.They exert anti-inflammatory and antioxidant effects
They enhance EPCs activity
[26]
DietIt affects the number of circulating EPCs [36, 37]
Dietary cocoa-derived flavonoidsThey increase number of functional circulating angiogenic cells [26]
Red ginseng extractsThey increase EPCs number [26]
Physical exerciseIt improves circulating EPCs levels. Prolonged 4-week exercise program improves EPCs functions. Maximal and endurance exercise influence the number of both EPCs and hematopoietic stem cells. [26]