Cardiac Fibroblast to Endothelial Cell Communication
A number of studies have demonstrated that CF can interact with EC and modify the expression of both pro- and anti-angiogenic factors. CF-secreted growth factors, including vascular endothelial growth factor (VEGF) and FGF, act on EC and stimulate angiogenesis.4
However, FC can also act in an inhibitory way. It has been shown in vitro that pigment epithelium-derived growth factor can be expressed by CF and can inhibit VEGF-induced tube formation.73 Moreover, the CF-secreted MMPs and TIMPs are involved in the process of angiogenesis and under certain conditions they can lead to promotion or inhibition of tube formation.74,75,76
CF and EC can also communicate by exchanging miRNAs. There is evidence that multiple miRNAs are expressed in endothelial cells and can lead to the promotion or inhibition of angiogenesis.77,78
Cardiac Myocyte to Endothelial Cell Communication
In the heart, EC outnumber CM at nearly a 3:1 ratio with virtually every CM bordering one or more capillary.79 CM paracrine signalling plays a key role in the dynamic regulation of the vascular tone but may also affect long term growth and development of coronary arterial, venous and lymphatic trees.29 Among the multiple paracrine signals the most important are VEGFs. When there is either an overexpression or a deficit in VEGF, the ultimate result is cardiac dysfunction.80 It is of note that although CM represent less than a third of the total cell number in the heart, cardiomyocyte-specific deletion of the VEGF-A gene results in a decrease in the entire VEGF mRNA synthesis to less than 15 % of normal, emphasising the role of CM as the main source of this growth factor in the myocardium.29 When mice were engineered with cardiac myocyte-specific deletion of VEGF, the result was thinned ventricular walls, decreased contractile function and lack of neural stimulation.81 VEGF is considerably increased in the ischemic myocardium, whereas the vasculature in ischemic myocardium is more sensitive to VEGF- induced vasodilatation.82,83
CM–EC communication is very important for the vascular adaptations that occur during cardiac hypertrophy. Myocardial hypertrophy induced by expression of Akt1 is a clinical setting that illustrates the importance of the balance between cardiac and vascular growth. Transgenic overexpression of activated Akt1 in CM resulted in a varied spectrum of phenotypes from myocardial hypertrophy with preserved systolic function to ventricular dilatation and failure.84 In a tetracycline-inducible cardiac myocyte-specific Akt1 transgenic mouse model, short-term (two weeks) induction of Akt1 expression resulted in physiological hypertrophy that was accompanied by analogous myocardial angiogenesis.85 However, Akt1 activation for longer periods of time resulted in a disproportionate increase in cardiac mass compared with the extent of angiogenesis and development of HF, presumably on the basis of an inadequate blood supply to cover the requirements of the hypertrophic myocardium.85 CM and EC are able to communicate electromechanically through gap junction proteins, such as Cx43.86 and it has been demonstrated that VEGF can affect Cx43 expression in CM, suggesting another VEGF-dependent pathway as a mode of interaction between myocardium and vasculature.80
Cell to Matrix Communication
The principal mediators of molecular dialogue between a cell and its extracellular matrix environment are integrins.87 They are heterodimeric cell-surface molecules that mediate signalling from the extracellular space into the cell through integrin-associated signalling and adaptor molecules such as focal adhesion kinase, integrin-linked kinase particularly interesting new cysteine-histidine rich protein and non-catalytic (region of) tyrosine kinase adaptor protein-2.87 Via these molecules, integrin signalling interacts with receptor tyrosine kinases signalling to regulate survival, proliferation and cell shape as well as polarity, adhesion, migration and differentiation. In the myocardium and blood vessels, the function and regulation of these molecules can be partially disturbed, leading to cardiovascular diseases such as cardiac hypertrophy and atherosclerosis. Integrin-mediated cell adhesion can be modulated by membrane-associated proteins such as the ADAMs (a desintegrin and metalloprotease). ADAMs can alter expression and function of growth factor receptors and, as a result, will then affect several biological processes, including angiogenesis and cardiac hypertrophy.29,88