Vascular smooth muscle cell differentiation in human cerebral vascular malformations.
OBJECTIVE
The pathogenesis of central nervous system vascular malformations likely involves the abnormal assembly, differentiation of vascular smooth muscle cells (VSMC), or both in association with dysmorphic vessel wall. We hypothesize that intracranial arteriovenous malformations (AVMs) and cerebral cavernous malformations (CCMs) exhibit distinct patterns of expression of molecular markers of differentiation and maturity of VSMCs. We further speculate that the unique VSMC phenotype in the different lesions is not necessarily maintained in cell culture.


METHODS
Paraffin-embedded sections of five AVMs, CCMs, and control brain tissues were stained immunohistochemically with antibodies to alpha-smooth muscle actin (alpha-SMA), myosin heavy chain, and smoothelin, a novel marker for contractile VSMC phenotype. Large (> or =100 microm) and small (<100 microm) vessels were counted and assessed for immunoexpression of each protein, then categorized according to expression of one or more of these markers. Cultured nonendothelial cells isolated from four other excised AVM and CCM lesions were assessed for immunoexpression of the same antibodies.


RESULTS
Alpha-SMA was universally expressed in all vessels in AVMs and in control brains. It was expressed in the subendothelial layer of 97% of large caverns and 85% of small caverns and in scattered intercavernous connective tissue fibrocytes in CCMs. Myosin heavy chain was expressed in the majority of brain and AVM vessels, except for normal veins, and in the subendothelial layer of more than half of the caverns in CCMs. Smoothelin expression was less prevalent in large vessels in AVMs than in control brains and was not found in any caverns in CCMs (large vessels in control brains, 40.9%; AVMs, 21.9%; CCMs, 0%; P < 0.0001). Cultured AVM and CCM nonendothelial cells expressed alpha-SMA, but myosin heavy chain was expressed weakly in cells from only one CCM. Smoothelin was negative in all cells.


CONCLUSIONS
We describe vessels with various stages of VSMC differentiation in AVMs and CCMs. The subendothelial layer of CCMs commonly expresses alpha-SMA and less commonly expresses myosin heavy chain. Expression of smoothelin was less prevalent in large AVM vessels than in normal brain, which may reflect the loss of contractile property associated with hemodynamic stress. It is difficult to evaluate VSMC differentiation in culture because of phenotypic change.
Uranishi
R
R
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.
Baev
N I
NI
Kim
J H
JH
Awad
I A
IA
D000199:Actins / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000276:immunology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology*; D046508:Culture Techniques; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D002538:Intracranial Arteriovenous Malformations / Q000175:diagnosis* / Q000276:immunology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000276:immunology / Q000601:surgery; D018995:Myosin Heavy Chains / Q000276:immunology; D024745:Smooth Muscle Myosins / Q000276:immunology
D000199:Actins; D000906:Antibodies; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains