Vascular Remodeling Following

In some ways, the term "vasospasm" is a misnomer, because it implies a reactive vascular tone that increases with a secondary vessel narrowing. There may be a critical difference between arterial vasospasm and cerebral vasospasm following SAH, because cerebral vessels lose their reactivity to most agents that act directly on vessel walls. For example, NO and nitroprusside normally act directly to dilate smooth muscle in vessel walls but have little effect in treating ischemic deficits due to cerebral vasospasm (49,58). An active tone increase implies a significant decrease in elasticity due to the contraction, yet the vessel wall actually becomes softer and more "putty-like" with cerebral vasospasm. It is unclear why the onset of delayed ischemic deficits due to cerebral vasospasm occurs several days after the initial SAH, when arterial spasm of cerebral blood vessels is often present on early arteriograms.

Arterial remodeling is a concept that was used in the past to describe any change in vessel wall structure. More recently, however, it has been used specifically to refer to a change in vessel cross-sectional area within the external elastic lamina (119). Cerebral vasospasm following SAH fits both these descriptions. Remodeling is an active process of structural alteration that involves changes in at least 4 cellular processes—cell growth, cell death, cell migration, and production or degradation of extracellular matrix (120). It is usually an adaptive response to long-term changes in hemodynamic conditions but may also result from vascular injury and contribute to the pathophysiology of vascular diseases. Inward remodeling denotes a reduction in vessel size. In low-flow states, or following endothelial or adventitial injury, accentuated production of mitogenic and fibrogenic growth factors mediates inward modeling by increasing SMC proliferation and collagen deposition and cross-linking (120). Some of the factors that regulate the growth of vascular cells in the pathogenesis of cerebral vasospasm are listed in Table 3.

Cerebral VSMC turnover begins rapidly after SAH (121). However, the SMCs may require a more potent stimulus to begin mitotic activity, such as the later combination of relative ischemia and the mix of growth factors available from the blood that coats the outer wall.

Table 3 Mediators of Vascular Remodeling Associated with Cerebral Vasospasm

Growth promoters Growth inhibitors

Platelet-derived growth factors (121) Nitric oxide (11)

Vascular endothelial growth factor (121) Heparin sulfate (122)

Transforming growth factor (123) Prostacyclines (PGI2) (110)

Basic fibroblast growth factor (124) Endothelin (125) Inflammatory cytokines: CD-18

(126, 127), IL-1ß,IL-6, and TNF-a (128) Thromboxane (129)

Figure 4 Scanning electron micrograph of a cerebral blood vessel in spasm (right) compared to a normal contralateral cerebral artery (left:) in a nonhuman primate. Source: From Ref. 130.

The vessel thickening would then correspond to a combination of (i) vessel necrosis of SMCs in the media and (ii) mitosis and hypertrophy of an underlying population of cells, which would lead to smooth muscle renewal and proliferation. The SMC proliferation would presumably then proceed over days to a few weeks, leading to a repopulation of the media and to resumption of normal vessel reactivity and caliber (Fig. 4).

Thus, the time course of delayed ischemic deficits due to cerebral vasospasm may be delayed due to the slow onset of smooth muscle necrosis over several days, which, together with the combination of mitotic activity and hypertrophy of remaining cells, markedly increases the width of the media, leading to shrinkage of the vessel lumen. The 5-day period may be an unfortunate superimposition of these 2 processes of necrosis with associated cell swelling and the secondary hypertrophy and mitotic activity of SMC turnover. This time period is compounded by the slow lysis of blood products by CSF and a correspondingly slow resumption of adequate vessel nutrition, presumably, as CSF adventitial pores are reopened or reconstituted.

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