Role of Microvascular Tone and Extracellular Matrix Contraction in the Regulation of Interstitial Fluid

Abstract

G enetic mutations that predispose to thoracic aortic aneurysms and aortic dissections (TAADs) affect structural components of the extracellular matrix (ECM), transmembrane structures involved in mechanical integrity, mechanosensing, and signal transduction, or intracellular components of the cell contractile apparatus. [1][2][3] Concepts and studies are being developed to explain how such alterations may impact the response of the aorta to hemodynamic stress and drive abnormal aortic remodeling. 4 Here, we propose a focus shift toward the small vessels (arterioles and vasa vasorum) to explain, based on current knowledge about the (patho)physiology of blood flow regulation and fluid dynamics, how alterations in ECM and the cell contractile apparatus may instigate the frightening process of aortic dissection. Microcirculatory Vascular Tone and the Autoregulation of Blood Flow: The Example of Myogenic ToneMicrocirculatory vascular tone is the main determinant of vascular resistance and ensures tissue perfusion in response to changing metabolic demands. An increase in pressure induces a rapid and reversible vasoconstriction of small resistance vessels, an intrinsic property because of their ability to develop myogenic tone (MT). 5 Besides protecting downstream capillaries from abrupt increases in blood pressure occurring in larger vessels, MT has a key role in the inward eutrophic vascular remodeling in response to a chronic rise in pressure.Pressure induces deformation of cell membrane proteins such as stretch-activated ion channels; conformational changes in matrix and cytoskeletal proteins; activation of ECM and integrins; and activation of various cellular junctions (Figure 1). Vascular smooth muscle cell (SMC) depolarization and calcium entry are necessary for the development of pressure-induced contraction and myogenic tone. Although the nature of the channel(s) involved in MT development remains debated, canonical transient receptor potential (TRP) channels are strong candidates. Interactions of TRP polycystin 1 and 2 (TRPP1 and TRPP2) with filamin A, an actin crosslinking protein, are critical for stretch-activated ion channel regulation and MT development.6 Indirect evidence for a role of chloride © 2016 American Heart Association, Inc. Abstract-The pathophysiology of aortic dissection is poorly understood, and its risk is resistant to medical treatment. Most studies have focused on a proposed pathogenic role of transforming growth factor-β in Marfan disease and related thoracic aortic aneurysms and aortic dissections. However, clinical testing of this concept using angiotensin II type 1 receptor antagonists to block transforming growth factor-β signaling fell short of promise. Genetic mutations that predispose to thoracic aortic aneurysms and aortic dissections affect components of the extracellular matrix and proteins involved in cellular force generation. Thus, a role for dysfunctional mechanosensing in abnormal aortic wall remodeling is emerging. However, how abnormal mechanosensing leads to aortic dis...

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