Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease

Abstract

Abstract-Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function. Such strategies may be useful in the treatment of chronic diseases such as hypertension, atherosclerosis, and ischemic artery disease, as well as in acute myocardial infarction and during open heart surgery for prevention of ischemia and reperfusion (I/R)-induced injury. The recent identification of putative endothelial progenitor cells in peripheral blood may allow the design of autologous cell-based strategies for neovascularization of ischemic tissues and for the repair of injured blood vessels and bioengineering of vascular prosthesis. "Proof-of-concept" for some of these strategies has been established in animal models of cardiovascular disease. However the successful translation of these novel strategies into clinical application will require further developments in vector and delivery technologies. Further characterization of the processes involved in mobilization, migration, homing, and incorporation of endothelial progenitor cells into the target tissues is necessary, and the optimal conditions for therapeutic application of these cells need to be defined and standardized. T he vascular endothelium (VE) plays a pivotal role in the regulation of vascular function and homeostasis. 1 In normal conditions, the VE elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation. [2][3][4] Pathological conditions caused by increased oxidative stress, hyperlipidemia, and inflammation lead to endothelial dysfunction, which is characterized by reduced availability of vasodilatory and anti-adhesion substances, such as nitric oxide (NO) and prostacyclin, and concomitant increases in vasoconstrictor and pro-adhesion factors such as endothelin-1, angiotensin II, and thromboxanes 4 (Figure 1). These changes lead to increased vascular tone, inflammatory cell and platelet adhesion, and proliferation of the media smooth muscle, which increase the occurrence of thrombosis and vascular occlusion. 3,4 Because of its central role in the pathogenesis of cardiovascular disease, the endothelium is an attractive therapeutic target for cardiovascular disease. 5 Genetic modulation of endothelial function may offer new opportunities to modify the course of common cardiovascular diseases such as hypertension, atherosclerosis, thrombosis, and ischemic artery disease, whereas the availability of endothelial progenitor cells (EPC) 6 may allow the design of cell-based strategies for rescue of ischemic tissue and rep...

Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries

“…Many cardiovascular diseases and dysfunctions would benefit from a targeted means to deliver drugs or genes to the endothelium [3]. Quantitative results (Fig.…”

“…Cardiovascular diseases that could benefit from this method of targeted delivery include diseased sites such as vulnerable atherosclerotic plaques and ischemic heart or peripheral tissue. Intracellular therapeutic targets such as NADPH oxidases or gene expression of eNOS in the endothelium could help control neointimal formation and restore vascular function [3,38]. Promoting angiogenesis by intracellular delivery or gene expression agents such as VEGF or FGF in the endothelium could also benefit ischemic injuries in the myocardium or peripheral vasculature [10].…”

“…Targeted drug and gene delivery to vascular endothelial cells (ECs) and smooth muscle cells (SMCs) has increasingly become a focus for treating cardiovascular diseases and dysfunctions, such as coronary artery disease, hypercholesterolemia, hypertension, and restenosis, because of the pivotal role of these cells in controlling and maintaining vascular functions [2][3][4]. In addition, targeted drug and gene delivery to the endothelium is being used to treat cancerous tumors by anti-vascular therapy [5] and myocardial and peripheral ischemia by promoting angiogenesis [6].…”

Image-guided, noninvasive, spatiotemporal control of gene expression

“…Several approaches for controlling gene expression have been proposed (1). Tissue-specific or disease-specific promoters can provide spatial control of gene expression (2,3), whereas small moleculedependent gene switches give temporal control (4,5). Alternatively, physical stimuli, such as ionizing radiation (6) and heat (7), offer the possibility of activating gene expression in deep tissue with excellent spatial definition, and they allow temporal control of the start of gene activation.…”

Vasopressors for cardiopulmonary resuscitation

“…Ischaemia also causes severe damage to the endothelium (Sapienza et al 1996). Endothelial damage results in reduced endothelial vasodilator responses (Sapienza et al 1996;Melo et al 2004) and thus in patients presenting with cardiac arrest, the vasoconstrictor properties of α2-adrenoceptors may dominate over the endothelial vasodilator effects (Kanagy 2005).…”