Presentación de Categorías de análisis a docentes

Organization of the arterial system during development is accomplished in a precise time and site-specific pattern by a complex interaction between hormones, growth factors, cytokines and hemodynamic forces (Bendeck et al., 1994; Hutana et al., 2007; Swee et al., 1995). These modulators delineate anatomically-defined differential gene expression that gives rise to the longitudinal variation in composition and geometry that characterizes the mature vascular tree. At the proximal end of the vascular tree, elastic fibres are present in abundance within the extracellular matrix (ECM) and the ratio of elastic fibres-to-collagenous fibres decreases toward

the periphery which is populated by small muscular arteries. Elastic fibres are arranged in thick, fenestrated concentric layers (Rosenbloom et al., 1993). Construction of a functional elastic fiber begins with the synthesis and deposition of the precursor molecule, tropoelastin, into the extracellular space by embryonic-type vascular smooth muscle cells (VSMCs) possessing synthetic properties. Once in the matrix, the rod-like structures are aligned within a microfibrillar

scaffold and covalently cross-linked to form the highly insoluble elastin protein (Debelle and Tamburro, 1999). The regulation of the single elastin gene is primarily exerted at the transcriptional level (Perrin et al., 1997; Swee et al., 1995). Insulin-like growth factor-1 (IGF-1) and interleukin – 1β are known enhancers of tropoelastin mRNA expression, whereas tumor necrosis factor -α (TNF-α) and transforming necrotic factor -α (TNF-α) downregulate gene transcription (Rich et al., 1992; Swee et al., 1995). Cortisol is a prominent example of a hormonal regulator acting upstream, which promotes elastin accumulation as well as collagen deposition (Rich et al., 1992; Bendeck et al., 1991). In addition to these hormones and growth factors, in vitro studies have shown tropoelastin mRNA expression and soluble elastin protein levels to be downregulated under conditions of hypoxia in cultured VSMCs (Durmowicz et al., 1991), whereas procollagen gene expression is upregulated in hypoxic VSMCs and myofibroblasts (van Vlimmeren et al., 2010). Further, reactive oxygen species prevent proper elastic fibre assembly in vitro through reduced cross-linked and interference in protein binding (Akhtar et al., 2010).

Collagenous fibers have high tensile strength and thus provide structural integrity to the tissues. Their presence in the arterial wall increases progressively toward the periphery where they play a part in the reflection properties of small arteries. In the heart, collagen proteins are the predominant components of the fibrillar network that supports individual cardiomyocytes and aligns the myofibrils within the myocyte (Graham and Trafford, 2008). In this way, collagen fibres contribute to systolic contraction through coordination of sarcomere shortening and are the primary determinants of compliance during diastole (Khan and Sheppard, 2006). Thus, proper functioning and health of the heart are largely dependent on the content and organization of collagen fibrils.

Whereas elastin derives from a single gene, several types of collagen proteins exist. The predominant collagens of the heart and vasculature are collagens Type I and III: the tensile

strength of the more abundant collagen Type I is substantially greater than that of collagen III (Qui et al., 2007). Once secreted into the extracellular matrix by synthetic VSMCs, the procollagen precursor is assembled into a triple helix and subsequently stabilized by posttranslational processing into a fibrillar unit (Van Der Rest et al., 1991). TGF-β1 and IGF-1 are known to stimulate collagen gene transcription, whereas interferon-γ, basic fibroblast growth factor (bFGF) and nitric oxide have been found to inhibit collagen synthesis (Ford et al., 1999; Kypreos and Sonenshein, 1998; Lawrence et al., 1994; Reiser et al., 1996).

Given that noncellular proteins are synthesized and secreted into the extracellular space by synthetic VSMCs, the deposition rate of collagen and elastin depend on the content of this cellular phenotype within the media (Durmowicz et al., 1996). VSMCs exhibiting high rates of proliferation and the ability to produce ECM molecules predominate in early gestation and gradually switch to the mature contractile cells whose principal function is regulation of vasomotor tone, blood pressure and blood flow distributions (Chern et al., 1995; Hutana et al., 2007). In the ovine fetus and human, this phenotypic transition largely occurs in the last third of pregnancy (Hutana et al., 2007; Owens et al., 2004). Therefore, ECM protein accumulation rises sharply with VSMC proliferation rates early in gestation, is curbed by cellular phenotypic maturation in late gestation and varies across vascular beds in relation to the synthetic to contractile phenotype ratio.

Modifications in the composition and geometry of the fetal vascular tree over the course of gestation also parallel hemodynamic changes, in order to redefine arterial mechanics in harmony with the new loading conditions. A general thickening of the arterial wall follows the developmental rise in MAP, increasing blood flow rates stimulate diameter enlargement and angiogenesis of the microvasculature respond to the growing perfusion demands of peripheral tissues (Bendeck et al., 1991; Cho et al., 1992). In late gestation, cyclic stretch induced by pulsatile flow becomes a potent stimulus of elastogenesis, whereas collagen synthesis appears unrelated to blood flow at this time. (Bendeck et al., 1994; Wells et al., 1999). Thus, elastin accumulates at a high rate in the aorta and other proximal arteries where its deformability is required for accommodation of pulsatile ventricular ejection.

During ovine and human pregnancies, collagen synthesis reaches a maximum early in gestation with a subsequent plateau, whereas elastin accumulates at a slower but steady rate from

early to late gestation (Bendeck et al., 1994; Berry et al., 1972). In late gestation, elastin synthesis begins to accelerate, reaching a peak in the immediate postnatal period. This accelerated elastin deposition is a key event in the critical phase of arterial remodeling that is initiated by a near-term rise in cortisol and subsequently follows the maturational changes in the hemodynamic environment. After birth, a brief and dramatic period of continued geometric remodeling and deposition of ECM components adapt the vasculature to the profound pressure and flow changes generated by the loss of the placenta, closing of fetal shunts and redistribution of cardiac output that accompany parturition and birth (Bendeck et al., 1994; Leung et al., 1977). Upon conclusion of this developmental remodeling, arterial structure and mechanics are suited to promote cardiovascular homeostasis in extrauterine life. Thereafter, rates of ECM protein synthesis decline rapidly. In fact, the half life of highly resilient mature elastin is 40 years (Shapiro et al. 1991) and its post-development biosynthesis is negligible under normal conditions (Mariencheck et al. 1995).