Variations in structural protein expression and endothelial cell proliferation in relation to clinical manifestations of cerebral cavernous malformations.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are associated with hemorrhagic proliferation of endothelial-lined vascular caverns, resulting in hemorrhagic stroke, epilepsy, and other neurological manifestations. We hypothesize that structural protein expression and endothelial cell proliferation markers within CCM lesions are different in the setting of various clinical manifestations. METHODS: The percentage of immunohistochemically stained caverns positive for collagen IV, fibronectin, laminin, alpha-smooth muscle actin, myosin, and smoothelin and the percentage of dividing endothelial cells within caverns were determined in 36 excised CCM surgical specimens. These were compared in CCMs with different multiplicity, location, and size in patients of different age, sex, seizure status, and hemorrhage status. RESULTS: Comparisons of seven lesion features and clinical manifestations with the fraction of caverns containing the structural proteins studied and endothelial cell proliferation demonstrated no significant differences. A possible exception was the difference (P < 0.05) in the fraction (mean +/- standard deviation) of positively stained caverns for collagen IV between adult (0.63 +/- 0.39) and pediatric patients (0.87 +/- 0.21) as well as fewer caverns with laminin expression in older patients. These trends did not sustain significance with Bonferroni's correction for multiple comparisons. CONCLUSION: The fraction of caverns containing the particular structural proteins studied and endothelial cell proliferation within caverns are not correlated with particular lesion features and clinical manifestations that were investigated in CCMs. The possible fewer fractions of caverns containing collagen IV and laminin in adult lesions compared with pediatric lesions may have implications for lesion regression and quiescence with age.

Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance.

Cerebrovascular malformations affect more than 3% of the population, exposing them to a lifetime risk of hemorrhagic stroke, seizures, and focal neurological deficits. Cerebral cavernous malformations (CCMs) exhibit an immature vessel wall, a brittle hemorrhagic tendency, and epileptogenesis, whereas arteriovenous malformations (AVMs) lack capillary beds and manifest apoplectic bleeding under high-flow conditions. There are also more benign venous anomalies, capillary malformations, and lesions with mixed and transitional features. Advances have been made toward understanding the natural history, radiological and pathological correlates, and clinical management. Yet, mechanisms of lesion genesis and clinical manifestations remain largely unknown, and the clinical behavior in individual patients is highly unpredictable. Lesion pathogenesis likely involves abnormal assembly or maintenance of blood vessels, resulting in dysmorphic vessel phenotypes. Familial CCM disease is in part caused by mutations in a cytoskeletal-related protein that is likely integral to interendothelial cell connectivity and maturation of the vascular wall. Rare familial forms of AVM disease have been correlated with two different transforming growth factor-beta receptor components, possibly causing disturbance in signaling during vascular assembly. Relevance of these mechanisms to the more common and otherwise identical sporadic CCM and AVM lesions is being explored. In this report, basic mechanisms of vasculogenesis and angiogenesis and how they possibly relate to the common cerebrovascular malformation lesions are reviewed. Novel concepts are discussed related to the cellular, molecular, and genetic substrates in CCM and AVM as well as to how this knowledge can be applied to predict, explain, and possibly modify clinical disease manifestations.

Further study of CD31 protein and messenger ribonucleic acid expression in human cerebral vascular malformations.

OBJECTIVE: In a previous study, we documented lower levels of immunoexpression of platelet endothelial cell (EC) adhesion molecule (CD31) in paraffin sections of cerebral cavernous malformations (CCMs), compared with arteriovenous malformations (AVMs) or normal brain tissue. We hypothesized that down-regulation of CD31 in CCMs might represent a distinctive phenotypic feature of ECs in this disease. To confirm this hypothesis, we further examined both protein and messenger ribonucleic acid (mRNA) expression of CD31, using immunohistochemical and in situ hybridization analyses, in fresh-frozen specimens of CCMs, AVMs, and control brain tissue. METHODS: Fresh-frozen sections of four AVMs, five CCMs, and four control brain tissue specimens obtained from surgical resections were immunohistochemically stained with antibodies to von Willebrand factor and two distinct epitopes of CD31. In two AVMs, four CCMs, and three control brain tissue samples from the aforementioned group, the expression of CD31 mRNA was also examined by using in situ hybridization. Large (>100-microm) and small (<100-microm) vessels were counted and assessed for protein and mRNA expression. RESULTS: In all tissues, ECs in the majority of vessels were immunopositive for CD31 with two distinct antibodies. CD31 mRNA was expressed in some but not all vessels in AVMs, CCMs, and control brain tissue. There were no statistically significant differences in CD31 protein or mRNA expression in CCMs, AVMs, and control brain tissue. CONCLUSION: The expression of CD31 in CCMs can be underestimated in paraffin sections. There does not seem to be a unique phenotypic differentiation of CD31 expression in ECs of CCMs or AVMs, compared with control brain tissue.