Faculty
| GARY L. BAUMBACH, M.D. Professor, Director of Neuropathology 200 Hawkins Drive - 5231D Roy Carver Pavilion Iowa City, IA 52242-1009 M.D. The University of Iowa, 1976 Ophthalmology and Pathology Residencies, The University of Iowa, 1976-80 Cardiovascular Research Fellowship, The University of Iowa, 1981-82 Neuropathology Fellowship, The University of Iowa, 1982-84 |
Vascular Hypertrophy
Vascular hypertrophy is a well-known complication of chronic hypertension. Several years ago, we proposed that cerebral vessels may also undergo “inward remodeling” during hypertension, which is defined as a reduction in vessel caliber due to rearrangement of components in the vessel wall as opposed to a reduction in distensibility or encroachment by hypertrophy. We and others have suggested that the impact of inward remodeling on vascular function may be equal to, or even greater than, that of hypertrophy.
A long-term objective in our laboratory is to examine mechanisms that contribute to cerebral vascular remodeling and hypertrophy during chronic hypertension. In the past, most efforts to understand mechanisms of altered vascular structure in hypertension focused on hypertrophy. An emerging concept is that inward remodeling is the primary response of small resistance arteries and arterioles by which they are able to adapt their structure to normalize wall stress and protect the microcirculation from the damaging effects of elevated pressure. Despite a recognition that the mechanisms underlying inward remodeling differ from those of hypertrophy, we are still in the early stages of clarifying our understanding of the pathogenesis of inward remodeling and how it differs from the pathogenesis of hypertrophy. Nevertheless, there is now strong evidence by us in cerebral arterioles in rat and mouse models of hypertension, as well as by others in mesenteric resistance arteries in spontaneously hypertensive rat and subcutaneous resistance arteries in human, that the renin-angiotensin system plays an important role in inward remodeling, as well as in hypertrophy.
Figure 1. A visual presentation of the multiple factors that are thought to play roles in Ang II-induced alterations in vascular structure beginning with activation of angiotensin-1 receptors (AT1R), followed by transactivation of EGF-R, and ending with vascular hypertrophy and/or remodeling. The red numerals are placed next to those factors that were utilized to formulate the overarching hypothesis.
Several provocative concepts have recently emerged that may lead to a greater understanding of mechanisms through which the renin-angiotensin system promotes inward remodeling and hypertrophy. First, a number of studies suggest that reactive oxygen species (ROS), such as superoxide (O2–) and hydrogen peroxide (H2O2), may play an important role in alterations of vascular structure induced by angiotensin II (Ang II). Second, numerous investigations suggest that Ang II may alter vascular structure via transactivation of receptor tyrosine kinases by Ang II type 1 (AT1) receptors. For example, inhibition of the receptor tyrosine kinase, epidermal growth factor receptor (EGF-R) also blocks Ang II-induced migration of vascular smooth muscle (VSM). This observation is important because migration of VSM within the vessel wall has been proposed as an important factor in inward remodeling. Third, the peroxisome proliferator acti¬vated receptor, PPARy, may exert protective effects in the vessel wall by preventing Ang II-induced alterations in vascular structure [42]. Based on these concepts we formulated the hypothesis that alterations in cerebral vascular structure induced by Ang II require a cascade of events that include inactivation of PPARγ, initiation of oxidative stress, and transactivation of EGF-R via steps that include ROS, c-Src and caveolin-1 (Fig. 1).