Spontaneous Rupture of the Internal Elastic Lamina in the Rat: The Manifestation of a Genetically Determined Factor Which May Be Linked to Vascular Fragility

Abstract

The spontaneous rupture of the internal elastic lamina (IEL) in various arteries occurs to different extents in different rat strains. We have quantified this phenomenon in the caudal and renal arteries and abdominal aorta in two normotensive inbred strains: the Brown Norway (BN) and Long Evans (LE) strains. At 5 weeks of age, BN rats of both sexes exhibited small numbers of interruptions in the IEL of the caudal artery, whereas LE rats did not. Postpubertal male and female BN rats presented large numbers of IEL interruptions in the caudal artery and significant numbers in the renal artery and abdominal aorta, whereas LE rats showed few in the caudal artery and none in the other arteries. Treatment with β -aminopropionitrile (BAPN, an inhibitor of lysyl oxidase, the enzyme involved in the formation of cross-links in elastin and collagen) increased the formation of IEL ruptures in both strains in the caudal and renal artery and in the abdominal aorta in BN rats, but not in the abdominal aorta of LE rats. Apart from IEL ruptures, which were more prevalent in BN rats, no differences were observed in the ultrastructure of the aortic elastic fibers between the two strains, either in controls or in BAPN-treated rats. When male rats of both strains were made hypertensive by unilateral nephrectomy and administration of deoxycorticosterone and salt, mortality was more precocious in the BN strain although blood pressure was significantly higher in the BN strain at only one time point. The incidence of cerebrovascular hemorrhage was 48% in BN rats and 0% in LE rats. Hypertension increased the formation of ruptures in the IEL in some arteries – to a greater extent in the BN than in the LE rats. These results raise the possibility that the propensity to spontaneous rupture of the IEL, which is in part genetically determined, may reflect a latent form of vascular fragility which becomes significant in hypertension, resulting in poor survival and susceptibility to cerebrovascular accidents.

Rupture of the internal elastic lamina and vascular fragility in stroke-prone spontaneously hypertensive rats.

“…11 Our present data on spontaneously hypertensive rats are in agreement with these previous results, suggesting that a high propensity for the spontaneous rupture of the arterial internal elastic lamina is related to increased vascular fragility, which under adverse conditions such as hypertension may lead to pathologic events.…”

“…10 In addition, the greater BAPN-induced premature rupture of the internal elastic lamina in the caudal artery of SHRSP than of SHR suggests that the inhibition of lysyl oxidase during growth had a greater adverse effect on the internal elastic lamina of the caudal artery in SHRSP. Previous studies have also reported different sensitivities to BAPN treatment, concerning both aortic aneurysm formation and rupture 24 and rupture of the internal elastic lamina, 11 in different substrains. In experiments in which BAPN was given from 5 or 10 weeks of age, most rats died of aortic rupture and not of stroke.…”

“…12 In addition, previous studies performed under conditions of hypercholesterolemia and hypertension have suggested that interruptions in the internal elastic lamina may represent areas of structural weakness in the arterial wall 13 " 15 and may be relevant to pathologic events later in life. 11 It has recently been shown in rats that thinning and fragmentation of the internal elastic lamina in some cerebral arteries occur at sites that later develop cerebral aneurysms under experimental conditions. 16 In addition, observations in human arteries have suggested that the size of defects in the internal elastic lamina is related to the degree of intimal thickening.…”

Chromosomal Mapping of Quantitative Trait Loci Controlling Elastin Content in Rat Aorta

“…16 According to our results, it is possible that BN alleles leading to a depletion in aortic elastin content may impact on blood pressure QTL detection and significance. In addition, the BN rat shows evidence of vascular abnormalities, including susceptibility to spontaneous ruptures of the abdominal aortic IEL, 7 which the LOU strain is devoid of. We particularly focused the genome-wide scan in the BNϫLOU cross on regions of rat chromosomes 5 and 10, which were previously associated with susceptibility to IEL rupture in a BNϫGH cross, 8 to test a possible relationship between this phenotype and variations in components of the aortic extracellular matrix.…”

“…7 The aortic elastin deficit in the BN rat is, at least in part, caused by decreased tropoelastin synthesis during the period of rapid growth. 5 Because the elastin gene polymorphism explains only a small part of differences between parental strains, it is thus probable that other genes account for the major proportion of the interstrain differences in aortic elastin content.…”