gms | German Medical Science

Objective: A major biomechanical contributor to maintain structural integrity of cerebral arteries throughout life is the protein elastin, which is predominantly localized in the internal elastic lamina (IEL). No data exists on the ability of the cerebrovasculature to synthesize elastin during ageing in response to hemodynamic challenge but it is well known that loss or degradation of the IEL results in e.g. cerebral aneurysm formation. We therefore investigated synthesis (i.e. elastogenesis) or loss of elastin in human cerebral arteries (CAs) throughout life and compared this to a non-malignant proliferative cerebrovascular disorder, i.e. brain arterio-venous malformations (AVMs).

Methods: Samples from cadaveric CAs or from patients undergoing surgical resection of brain AVMs were processed to ultra-purify elastin. The age of purified elastin extracted from cerebral arteries or from AVMs was relatively estimated using aspartic acid racemization (AAR) or absolutely measured using the ¹⁴C bomb-pulse technique. We constructed a mathematical model of ¹⁴C biological incorporation using variable elastin formation and degradation rates in human CAs to model physiological elastin turnover during life. We then applied this model to explain differences in elastin age in brain AVMs.

Results: A total of 65 CAs and 20 extra cerebral arteries collected from individuals during judicial autopsies aged between 9 months and 104 years as well 25 incidental or ruptured brain AVMs were processed to yield ultra-purified elastin for further analysis. Using a model based on an initial-value transport equation system in which elastin expanded from birth to age 19 and continued in steady state throughout life, we calculated the annual turnover rate of 1.7% for elastin in CAs. Conversely, the age of elastin in AVMs was tightly associated with date of resection rather than date of birth of the individual patient being treated for the AVM; the average elastin age in AVMs was 2-4 years. There was no evident difference (p=0.175, two way t-test between) in F¹⁴C levels (i.e. age of elastin) in ruptured (n=9) versus unruptured (n=4) AVMs.

Conclusion: Our data resulted in the first ever mathematical model to describe elastin turnover in arteries of the human brain: After adulthood has been reached, elastogenesis and degradation in CAs continue throughout life at low rates. Our data indicated that human CAs have minimal capacity to compensate structural damage derived from elastin breakdown or increased accumulated damage. In contrast, a hallmark of brain AVMs is elastogenesis, which indicates that AVMs are of non-congenital origin and/or undergo rapid vascular turnover. Even though our findings cannot elucidate the causality of elastogenesis in brain AVMs, they have important implications for the current understanding and potential molecular treatment of cerebrovascular disorders, including cerebral aneurysms.