Mechanical Forces Acting on Vascular Endothelium

Mechanical forces in the form of shear stress imposed by blood flow and mechanical strain resulting from heart propulsions and hydrostatic pressure affect all vasculature in the organism and play an important role in physiological and pathological vascular responses. However, differences in hemodynamics and additional mechanical forces resulting from respiratory cycles form unique mechanical environment experienced by pulmonary vascular endothelial cells (ECs). In systemic circulation, vascular endothelium experience higher hydrostatic pressure and shear rates (15-40 dyn/cm2), and estimated amplitude of vessel distension caused by heart propulsions ranges within 5 to 10 percent. Pulmonary circulation is characterized by lower hydrostatic pressure and shear stress. Whereas a large body of literature exists on the effects of shear stress in endothelial cells, very little is known about effects of mechanical stretch on pulmonary endothelium. Although the degree of lung cell stretching is not known precisely in critically ill patients submitted to mechanical ventilation, many in vitro studies have used cyclic uniaxial strain in the range of 5 to 30 percent elongation to mimic physiological and pathological reactions of cell stretching, which correlated with vascular stretching caused by mechanical ventilation at high tidal volumes (20-25%). Thus, cyclic strain (or stretch) is more prominent factor in the cells of the alveolar capillaries in the lung, whereas shear forces may have differential effects on various potions of the vascular bed with gradient decline from the arterial endothelium in systemic circulation to the capillaries from systemic and pulmonary vascular beds.

Shear Stress

In large arteries, the mean wall shear stress is typically in the range of 20 to 40 dyn/cm2 in the regions of uniform geometry and away from branch vessels. Estimated shear rates in the pulmonary artery are 10 to 20 dyn/cm2. The actual values of shear stress for different segments of human pulmonary vascular tree have not been yet determined; however, calculations using data obtained from animal models suggest that the range of shear stress in lung arterial tree is 0.1 to 4 dyn/cm2.

The pathological role of disturbed flow in atherogenesis is manifested by the focal distribution of atherosclerotic lesions in the bifurcations and curved regions of the arterial tree where blood flow is disturbed by flow separation, and the rates of shear stress are low and unsteady in these lesion-prone areas. Direct correlation was found between decreased shear rates and turbulent flow with increased local permeability of ECs. Experimental manipulations with flow rates and patterns in situ and in cell culture models suggest increased endothelial permeability and lipid deposition in the areas of reduced or disturbed laminar flow and completely preserved barrier properties of endothelial mono-layer in the areas with normal or elevated flow. Although both pulmonary and systemic circulation are constantly exposed to varying levels of shear, lung endothelial cells experience variable flow patterns in vivo under physiological and pathological conditions that are dictated by unique features of the pulmonary circulation. For example, the distribution of blood flow throughout the human pulmonary vasculature is nonuniform and decreases from the base to the apex of the lung. In pathological situations, such as severe hypovolemia or mechanical ventilation at excessive airway pressure, apical pulmonary arterial pressures may fall below alveolar pressures, resulting in capillary collapse and cessation of blood flow. Cessation of pulmonary flow through defined segments is observed after thromboembolism, or in response to hypoxic vasoconstriction, a condition unique to the pulmonary circulation, which may result in capillary collapse. Thus, the differences in systemic and pulmonary flow patterns may dictate different mechanisms of flow-induced regulation of endothelial functions in these systems.

Mechanical Strain

Mechanical strain experienced by endothelial cells from systemic and pulmonary circulation is a superposition of pulsatile and tonic components. Tensile stress is imposed on the vascular wall by hydrostatic pressure counteracted by tonic contraction of vascular smooth muscle cells and elastic components. In addition, cyclic stretch is imposed by heart propulsions. Pulsatile distension of the arterial wall in systemic circulation normally does not exceed 10 percent to 12 percent, whereas various vasomotor reactions may change diameter of smaller caliber "resistance" arteries may reach 60 percent of initial diameter or more and last minutes or hours. Chronically increased blood pressure and vascular transmural stress activates vascular cell proliferation and collagen and fibronectin synthesis, which results in thickening of the vascular wall as a feature of hypertension-induced vascular remodeling. Direct measurements of interstitial/vascular distension in the mechanically ventilated lung are not currently available because of the complexity of local distension patterns in the lung parenchyma further complicated by uneven regional lung distension observed during inflammation and lung injury. However, studies by S. Margulies' group [1] suggest that if lung volume increases from 40 to 100 percent of total lung capacity, alveolar epithelial cell basal surface area increases by 34 to 35 percent. Pathological lung distension observed in ventilator-induced lung injury (VILI) induces alveolar and vascular barrier dysfunction, increased inflammatory cytokine production, macrophage activation, and acute inflammation that may culminate in pulmonary edema or acute respiratory distress syndrome. Several groups including ours have established cell culture models related to in vivo VILI conditions and reproduced in cell culture models cellular responses such as cytokine production and exacerbation of agonist-induced endothelial barrier dysfunction by high-amplitude cyclic stretch observed in the injured lung (Birukov et al., 2003; Dos Santos and Slutsky, 2000; Pugin et al., 1998; Vla-hakis et al., 1999) [2-5]. These models are now intensively utilized in studies of pathophysiological mechanotransduc-tion and gene expression, which will be described later.

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