**2.4 Regulation: Signaling pathways**

Different, complex and not fully understood molecular pathways activate the changes described in the pathobiology of VC [4]. Many of those factors have more than one implication in VC and a lot of them interact with each other. There is a "perfect storm" [25, 49] behind VC. Hereby we analyze the mechanism and the signals involved with the onset of VC.


6 were described as involved in the pathway resulting in activation of Runx2 and Osterix by ß-catenin, in a way not yet clarified [13, 58]. There are many proteins to regulate Wnt cascade like sclerostin, which binds to the membrane receptor thus inhibiting it, and **MSX-2** homeobox that promotes paracrine Wnt signals [13, 49]. It is also implied in the cell-cycle, proliferation, lineage commitment and regulation of apoptosis and its activation is related to TNF-α, oxidative stress and hyperphosphatemia [13, 58].


Vitamin D can induce such activity. ATP Binding Cassette Subfamily C member 6 (ABCC6) and ecto-5′-nucleotidase (NT5E) genes encode for the intermediary enzymes in the formation and degradation of ATP to AMP and ultimately, adenosine; These several enzymes are related to genetic calcifying diseases [58].

• **Phosphate and calcium status** – increased concentrations of these ions result in the formation of either crystals or nanoparticles with proteins, as referred. Transient or continuous elevated extracellular phosphate, in any form, has cytotoxicity consequences: it can lead to apoptosis because of ROS burden, an important calcifying event; and it can activate the digesting MMPs responsible for elastolysis [4, 13, 75]. Elevated calcium concentrations facilitate phosphate entry and is linked to calcification even in normal phosphoric quantities. Both calcium and Pi are related with Runx2 activation [13, 17, 47]. HA crystals,

*Vascular Calcification and Cardiovascular Risk in Chronic Kidney Disease: A Problem That Is… DOI: http://dx.doi.org/10.5772/intechopen.99886*

nanoparticles or free phosphate can render the same results. In fact, it has been proposed that cell-internalized CPPs with low fetuin-A are the most common event and that they can be detected circulating in CKD patients' blood, as they do not in healthy individuals [32].

• **MicroRNAs (miRNAs)** – regulate gene expression by targeting translated mRNAs and altering its traducing to proteins. EVs are known to have miRNAs and there have been new studies on this matter [47].

On the other hand, it is of notice that for the installation of VC, there is a role to be played by the concomitant loss of several osteogenesis antagonizing molecules, such as [58]:


A complex myriad of factors may offend the vessel wall's cells such as: elastolysis, cytokines, ROS, oxidized lipids, glucose, uremic molecules, BMPs and circulating calciprotein particles (CCPs). These will ignite signaling pathways like the Wnt pathway, resulting in the trans-differentiation of VSCM by the action

#### **Figure 1.**

*Mechanisms of vascular calcification. ALP: Alkaline phosphatase; Fet-A: Fetuin-A; GRP: Gla-rich protein; MGP: Matrix Gla protein; OPN: Osteopontin; OPG: Osteoprotegerin; PPi: Pyrophosphate; RANK-L: Receptor activator of nuclear factor* Κ*B- ligand; VC: Vascular calcification; VSMC: Vascular smooth muscle cells. (Adapted from Dellegrottaglie et al. [28].)*

of transcription factor Runx2. Deposition of minerals is promoted in the matrix, either in vesicles or apoptotic bodies. As this occurs, a loss of calcification inhibitors will pose no obstruction to the process.

Ultimately, the stiffness caused by this remodeling of the medial layer will result in ventricular hypertrophy [19, 49].

**Figure 1** resumes the before mentioned pathways and mechanisms implied in the vascular calcification process.
