The cellular components of the cardiovascular, digestive, and urinary systems elicit adaptive responses to mechanical/pressure overload acutely by retooling their cytoskeletal structures (i.e. increasing actin polymerization rate and contractile protein levels) and chronically by remodeling their extracellular environment. These compensatory responses are associated with the activation of angiogenesis to meet increased metabolic demands and improve tissue perfusion (1, 2). In the absence of angiogenesis, hypertrophic growth increases diffusion distance around microvessels resulting in reduced oxygen supply and hypoxia, altered muscle contractility, and organ failure. Clearly, an unsatisfactory/ insufficient vascularization is an important restraint on the adaptive capabilities of mechanically overloaded tissues.Neovascularization in mechanically challenged smooth muscle-rich organs in particular is promoted by various mechanoresponsive angiogenic factors including CCN1, formerly known as cysteine-rich protein 61 (Cyr61), a functionally multifaceted matricellular protein that appears in the extracellular environment particularly during development and pathological states (3, 4). The CCN1 protein acts either independently or in concert with vascular endothelial growth factor to drive sprouting and branching of new blood vessels and provides protection against oxidative stress (5, 6). Essentially, the CCN1 protein enhances angiogenesis by providing structural integrity to blood vessels, supplying necessary growth factors for endothelial and perivascular cells, and modulating extracellular matrix synthesis and degradation. Targeted disruption of the CCN1 gene leads to early or perinatal lethality in mice due to impaired vessel formation and/or branching (7). The CCN1 proangiogenic properties have further been demonstrated in different models of angiogenesis including rabbit ischemic hind limb and rat cornea models in which CCN1 improves angiogenesis and collateral blood flow to an even larger extent than vascular endothelial growth factor (8, 9).Mechanical strain typified by tension, stretch, shear, and pressure largely controls the expression of the CCN1 gene, although little is known about the molecular mechanisms involved (10). CCN1 was induced in mechanically stimulated myocardial fibroblasts and in smooth muscle cells (SMCs) 2 2 h

Although overall survival was not significantly greater for the combination, EM-V was superior to V for time to progression and PSA improvement. These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC.