Negative Feedback Mechanisms in the Architecture and Function of the Connective and Cardiovascular Tissues

NEGATIVE FEEDBACK MECHANISMS IN THE ARCHITECTURE AND FUNCTION OF THE CONNECTIVE AND CARDIOVASCULAR TISSUES SIMON RODBARD* The determination ofthe forms and structures ofthe cardiovascular and connective systems is generally attributed to genetic forces and to their modifications by hormonal and pathologic processes. However, numerous workers have noted that the structural components ofthe connective tissues of the body are remarkably adapted to the continually changing mechanicalforces which must be borne by them. On the basis ofstudies of the development ofthe blood vessels in the embryonic chick, Thoma [i] suggested three-quarters ofa century ago thatvascular structure was modified by mechanical forces. He concluded that (a) vascular caliber varied with the rate ofblood flow, (b) vessel length depended on the tension exerted by the tetherings ofthe vessels, (c) vessel-wall thickness varied with the tension (= pressure X radius) in its wall, and (d) an increase in intracapillary pressure induced the formation ofnew capillaries. Some workers have explored various aspects of the role of mechanical forces in vessel structure and in tissue cultures [2]. However, the greatest effort has been directed to the study ofbiochemical and pathological changes in the vessels . Our studies on animals and on models support the thesis that mechanical forces induce changes in the structure ofblood vessels [3-9] and ofother connective tissues, including the bones, muscles, and fascia of the body. While an abundant though dispersed literature reports data which can be shown to be in substantial support ofthe hypothesis presented below, the * Department ofCardiology, City ofHope Medical Center, Duarte, California 91010. This study was aided by grant HE 08721 from the National Heart Institute ofthe United States Public Health Service. 507 data to be presented provide a basis for a general statement on such interactions between stream and vessel structure. Definitive proof for many aspects ofthis thesis is lacking at present. Passive effects of the stream on the wall have been demonstrated in compliance studies of elastic vessels and in studies of the effects of flow through collapsible vessels, through channels ofplaster ofParis or in tubes ofdeformable silicone. Flow at low velocities produces no effects on such channels. However, at certain velocities, the walls ofthe vessels not only erode as in the hydrologie cutting ofchannels, but the walls may intrude into the lumen at sites ofreduced pressure. The stream can form meanders, generate stenotic lesions, form excrescences and emboli, produce "dissections " ofthe wall, "grow" cushions and valvelike formations, and determine other events which bear striking similitude to normal and pathological structures seen in blood vessels [3,4]. Many effects similar to the foregoing are readily observed in the embryonic heart and blood vessels. For example, cushions of cardiac jelly lined by a single layer ofendothelial cells appear early in development at the orifices between the successive chambers of the embryonic heart [10, 11]. During flow through an orifice, the laws ofconservation ofmass and energy determine a concentration ofthe stream lines, reducing the pressure against the cushions of deformable ground substance. As a result, the cushions tend to increase in size. When flow is pulsatile, hydrodynamic forces further transform the gelatinous cushions into valvelike structures which are oriented to prevent regurgitant flow. For a number ofyears, this laboratory has examined the thesis that the cells of the cardiovascular system are sensors for specific mechanical stresses such as tension, compression, drag, friction, and their rates of change. The cells appear to respond by elaborating and arranging specific structural materials which they utilize to relieve themselves of the stress. The evidence to be presented supports the concept that these responses of the cells determine many ofthe normal patterns ofdevelopment, growth, organization, and adaptation of the vascular system to changing stresses. Under other conditions, some of which are discussed below, the active responses to such forces may result in changes in the connective tissues and in the cardiovascular system which the affected individual may consider to be undesirable. In die following paragraphs, the headings indicate the mechanical 508 Simon Rodbard · Connective and Cardiovascular Tissues Perspectives in Biology and Medicine · Summer 1970 Stresses in operation and the negative feedback mechanisms which induce the tissue changes which result in the elimination of the effects of these stresses on the tissues. These relationships are...