1. Chapter 14 PART IV: Molecular Pathology of Human Disease Molecular Basis of Cardiovascular Disease Companion site for Molecular Pathology Author: William B. Coleman and Gregory J. Tsongalis

2. Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 2 Phase contrast photomicrographs of VICs in monolayer culture at moderate (a), confluent (b), and superconfluent (c) densities. Note the elongated morphology in (a) and the overlapping growth pattern in (b) as indicated by arrows. Scale bar represents 20 μm. Magnification 200x. Reprinted from Am J Pathol. 2007; 171:1407–1418 with permission from the American Society for Investigative Pathology. FIGURE 14.1

3. Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 3 The current literature describes numerous VIC functions which can be conveniently organized into five phenotypes: Embryonic progenitor endothelial/mesenchymal cells, quiescent VICs (qVICs), activated VICs (aVICs), stem cell derived progenitor VICs (pVICs), and osteoblastic VICs (obVICs). These represent specific sets of VIC functions in normal valve physiology and pathophysiology. Embryonic progenitor endothelial/mesenchymal cells undergo endothelial-mesenchymal transformation in fetal development to give rise to aVIC and/or qVICs resident in the normal heart valve. The VICs undergoing the transformation do have features of aVICs, including migration, proliferation, and matrix synthesis. When the heart valve is subjected to an insult, be it abnormal hemodynamic/mechanical stress or pathological injury, qVICs become activated, giving rise to aVICs which participate in repair and remodeling of the valve. pVICs including bone marrow-derived cells, circulating cells, and resident valvular progenitor cells are another source of aVICs in the adult. The relationship between bone marrow, circulating, and resident pVICs is unknown. Under conditions promoting valve calcification, such as in the presence of osteogenic and chondrogenic factors, qVICs can undergo osteoblastic differentiation into obVICs. It is possible that obVICs are derived from pVICs. obVICs actively participate in the valve calcification process. Compartmentalizing VIC function into distinct phenotypes recognizes as well the transient behavior of VIC phenotypes. The hatched arrows depict possible transitions for which there is no solid evidence currently. Reprinted from Am J Pathol. 2007; 171:1407–1418 with permission from the American Society for Investigative Pathology. FIGURE 14.2

4. Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 4 Model of latent TGFβ activation and TGFβ signaling in VICs upon experimental wounding in a tissue culture model. VICs in the nonwounded monolayers are quiescent. Wounding leads to activation of latent TGFβ in the extracellular environment of VICs at the wound edge, possibly through changes in integrins or secretion of TGFβ activation proteases. Active TGFβ signals through its cell surface receptors leading to myofibroblast differentiation giving rise to activated VICs at the wound edge. FIGURE 14.3

5. Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 5 The normal adult heart valve is well adapted to its physiological environment, able to withstand the unique hemodynamic/mechanical stresses under normal conditions. Under conditions of pathological injury or abnormal hemodynamic/mechanical stresses, VICs become activated through activation of VECs and by inflammation and associated cytokine and chemokine signals. Macrophages will also be activated. aVICs increase matrix synthesis; upregulate expression of matrix remodeling enzymes; migrate, proliferate and undergo apoptosis; as well as undergo osteoblast transformation. These processes are regulated by a variety of factors, several secreted by the aVIC. If the aVICs continue to promote these cellular processes, angiogenesis, chronic inflammation, fibrosis, and calcification result, leading to progressive clinical valve disease. Reprinted from Am J Pathol. 2007; 171:1407–1418 with permission from the American Society for Investigative Pathology. FIGURE 14.4

6. Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 6 FIGURE 14.5