Now, when we're talking about some of the
causes for aortic aneurysm and dissection.
Hypertension is going
to be a major cause.
the vascular tone,
and the patency of the
vessels of the vasa vasorum.
And if you have high systemic
you will get a progressive
of the arterioles of
the the vasa vasorum,
which means that you will
have progressive ischemia
of that watershed zone between
where the vessels the vasa vasorum
perfuse the outer two
thirds of the media
and how far blood can diffuse or oxygen
can diffuse from the luminal contents.
And that area is
now greyed out here.
And with hypertension, we're going
to have a zone of smooth muscle cells
that will ultimately
become ischemic and die.
And if they are dead, they're
obviously not making their synthetic,
they're not doing their
We can also have inflammation
of the vasa vasorum
surround each one of our
arterioles in the vasa vasorum,
you now see little blue dots,
those are inflammatory cells,
and diseases such as syphilis, tertiary
syphilis will cause an endarteritis.
So the arterioles, of the
vasa vasorum and arterioles
That is due to inflammation because the
syphilitic organisms set up shop there.
And when the immune system recognizes that
they have infected and invaded those vessels,
they come in and attack.
That attack that inflammatory
process trying to get rid
of the treponemes that
are causing the syphilis
will actually lead to
destruction of the vessel.
And again, the outer two-thirds
of the media are going to die
as a consequence of inflammation
of the vasa vasorum.
Here's the other
part of the equation.
If we make the wall,
the innermost intima of the vessel
too thick with
such as indicated here now
on the lower right hand side,
that's going to increase
the diffusion distance.
And that same watershed
zone the inner third,
and the watershed zone of the media is
going to die become ischemic and die,
not making its synthetic materials to
maintain the integrity of the media.
And then you can have infections,
so called mycotic aneurysms.
When we say mycotic it doesn't mean fungus;
it happens to mean just infection in this case,
and infections with
reactive oxygen species
and all the things that happen
with inflammation and an infection
will cause necrosis
of the media as well,
which will impact clearly the
integrity of the aortic wall.
And then let's get
back to our TGF-beta.
TGF-beta receptor story having to
do with the fibrillin microfibrils.
So there are a number of
diseases where we have
abnormal synthetic function
of the smooth muscle cells,
not because they're ischemic,
not because they're infected,
not because the vessels are infected, but
there's an intrinsic hereditable defect
leading to changes in the normal
smooth muscle cell proliferation
and protein synthesis.
An example of this
is Marfan disease.
So there is defective
Fibrillin is going to
be one of the major ways
that we hold as a
TGF-beta is being secreted
by the smooth muscle cells.
And it is floating around
and normally we sop it up,
we hold it in an inactive form associated
with the fibrillin microfibrils.
If we have defective
suddenly we have too much
TGF-beta floating around,
and then we're going to get too much
activation of the TGF-beta receptors,
and we're going to have
defective elastic tissue
and collagen synthesis by
the smooth muscle cells.
So that's how Marfan works.
Loeys-Dietz is another heritable
form causing aortic aneurysms.
In that case, we have normal
levels of TGF-beta production.
We even have normal fibrillin.
So we're able to kind of bind
up all the free TGF-beta,
but what we have are
mutant TGF beta receptors
that are constitutively active.
So they will now signal
the smooth muscle cells
in the absence of external
TGF-beta floating around
and now we get the same synthetic
defect by those muscle cells
not making collagen appropriately,
not making elastic tissue appropriately.
Ehlers-Danlos is something that's
outside of the TGF-beta axis.
Ehlers-Danlos are defects
in the collagen synthesis.
So you see that kind
of green double helix.
Well now it's fragmented because we
have aberrant collagen synthesis,
and clearly that's going to make for a
less robust aortic wall construction.
We can also have metabolic defects
that give us the same problem
associated with abnormal or
insufficient collagen synthesis.
And vitamin C deficiency, which is going to
be very important for collagen crosslinking
can be a cause for aortic aneurysms,
abnormal weakness of the media in the aorta.
We can also have as associated
with certain inflammatory diseases
such as abdominal aortic
aneurysm, that's what AAA is.
We can cause changes in
extracellular matrix turnover
due to mediators that are acting
now on the smooth muscle cells.
And that can include things like TGF-beta
elaborated by the inflammatory cells.
But interleukin four, interferon gamma, tumour
necrosis factor — there is a whole variety of things
that will alter the smooth
muscle cell repertoire
and the turnover of the
extracellular matrix proteins.
So inflammation can be another
cause for aortic aneurysm.
What does this look like?
So when the aorta fails or when it
doesn't make the appropriate matrix,
we get what is called
cystic medial degeneration.
It's truly it's not cysts but it's
an increase in extracellular matrix
that is not collagen
that is not elastin,
which is very rich in
So it's something that
picks up a lot of water,
they're very sulfated,
they pick up water, and they give kind of a blue-gray cystic
appearance when we look at them by Hematoxylin and eosin staining (H&E).
You can see the soon
muscle cells interspersed.
And actually, if we were going
to do an elastic tissue stain,
we would also see that that
is, is being fragmented.
The smooth muscle cells in cystic medial
degeneration or cystic degeneration
are not making their normal
complement of proteins,
they're not making normal
levels of fibrillin,
not making normal levels of type
I and type III collagen,
they're not making
normal elastic tissue.
They're making the sulfated
which don't have much
Any form of aortic injury
can go to this final
kind of common pathway in terms of
the way it looks histologically.
So you get the
proteoglycan rich matrix
that looks cystic that's
highlighted there in green.
And you get fragmentation.
This is the normal
kind of density,
indicated there underneath the
asterisk of the of the elastic tissue,
you tend to get nice, black lamellae. This is within elastic
tissue stain, nice black lamellae of the elastic tissue.
But that's fragmented up there in the
circle, we don't have the same density,
we don't have the same layering,
the smooth muscles cells in
that location are degenerating,
they're not making
the right matrix.
As a result of that,
this aorta that needs to withstand
120 millimetres of mercury or more
now doesn't have the
structural integrity to do that.
And with each beat of the heart,
in the absence of adequate elastic
tissue or adequate collagen.
Now the aorta is going to go
so it's going to dilate up.
That's an aneurysm.