Embryology of the Cranial Circulation

(1)

Nuffield Department of Surgical Sciences, Oxford University, Oxford, UK

Preamble

From whence we come…

What is the value of studying embryology when variant and anomalous vessels are so uncommon? Surely we always rely on a detailed analysis of each patient’s vascular anatomy to guide endovascular treatments.

For me, anatomy is like a city street map. To be more precise, it is like the streets and roads of London, where I grew up. As a child I learnt to navigate those within walking distance of home and knew only main routes taken by car or bus to visit friends, shopping and other excursions. This familiarity of use fundamentally changed when I learnt to drive and was no longer a passive observer. Now, consider the role of chauffeur extended to showing visitors around my city. My priority changed, from learning shortcuts, good parking places and congestion avoidance (though all very useful to the city guide), to pointing out the sites and important historic places.

We should learn the history of the routes we travel to deliver our therapy with the intimacy of the London cab driver and be prepared for the obscure address which few but they would know. In embryology we have a chance to marvel at the compressed evolution of foetal development. By learning about those processes, we are delighted when recognising throwbacks and anomalies, which, like historic sites, provide evidence of ‘from whence we come’.

In this tutorial the embryology of cranial vascular development is presented in a simplified overview. Unlike other tutorials, the text contains few citations, since the descriptions are largely based on the classic works of D. H. Padget which are listed with other source texts, at the end of the tutorial. Readers may find it useful to read this tutorial in conjunction with Tutorials 2 and 7 because it represents the precursor vascular anatomy covered in the subsequent chapters.

1.1 Definitions of Terms Used in Embryology

Embryonic period: The embryonic period is defined as the first 8 weeks after fertilisation or the first 10 weeks after the last menstrual period which is the gestational age. It is the time when tissues differentiate to form the principle organs (i.e. organogenesis).

Phylogeny: This term refers to the sequence of events involved in the evolutionary development of a species or taxonomic group of organisms.
Ontogeny: Refers to the development of an individual organism.
Foetal period: The time from the end of the embryonic period until birth.

Anomaly and malformation: An anomaly is a deviation from the common or normal, whilst malformation means badly formed and implies a defective structure. Both should be distinguished from abnormality which refers to a given anatomical configuration that is pathological.

Variation: Is a modification or different form of something and is used to describe divergence from the usual or expected growth pattern. It does not imply that the result is harmful to the individual.

1.1.1 Timelines in the Embryonic Period

The first 4 weeks of the embryonic period precedes the development of the heart and circulation, so our interest in the development of cranial vessels begins at about 22 days, i.e. the start of the fourth week after fertilisation. The relevant milestones in the remaining embryonic period are shown in Table 1.1.

Table 1.1

Events expected during the second half of the embryonic period

Embryonic period: 4th–8th week
4th week (22–28 days from fertilisation = 4 mm CRL)
Heartbeat begins
Branchial arches form
The neural tube closes (day 24)
The ears begin to form as otic pits
5th week (29–35 days from fertilisation = 9 mm CRL)
Optic cups form
Nasal pits form
The brain divides into five vesicles
Rudimentary blood flow starts
6th week (36–42 days from fertilisation = 13 mm CRL)
Brain grows
Lymphatic system appears
7th week (43–49 days from fertilisation = 18 mm CRL)
Foetal heartbeat detectable
Spontaneous limb movements seen on ultrasound scan
Foundation of all essential organs in place
8th week (49–56 days from fertilisation = 40 mm CRL)
Adult pattern of cranial arteries established

CRL crown rump length: This measure is variable and given only a guide to the size of the foetus at each stage.

1.1.2 General Concepts in Vessel Development

Before reviewing the recognised stages of embryonic cranial vessel development, it is worth first considering how blood vessels grow and adapt to supply tissues. Where no blood vessels exist, as in the embryo, their growth is termed vasculogenesis. Growth of existing blood vessels is by angiogenesis:

(a)

Vasculogenesis occurs from clusters of endothelial cells, which develop from precursor cells, called angioblasts. Endothelial cells form vessels that grow and differentiate under the influence of growth factors and the extracellular matrix. These local clues include signal proteins, adventitial fibroblasts, pericytes and smooth muscle cells. A primary network forms, by a combination of apoptosis and proliferation. Once blood flow is established, it stimulates selective remodelling of vessels by angiogenesis in response to the tissue need. Once complete vasculogenesis does not occur again under normal conditions, but certain steps may be reactivated under pathological conditions, such as tumour growth.
(b)

Angiogenesis refers to the growth of new vessels in response to tissue growth, wound healing and the formation of granulation tissue. There are two types: sprouting and non-sprouting or splitting angiogenesis.

Sprouting angiogenesis is the growth of new vessel from parent vessels, similar to the growth of branches on a plant. It occurs in a well-described series of events initiated by the activation of endothelial cell receptors and the release of proteases that degrade the basement membrane allowing endothelial cells into the adjacent matrix. These cells then ‘spout’ through the matrix towards the source of the angiogenic stimulus. They migrate in tandem because of adhesion molecules called integrins and form new vessels linking adjacent vessels. Vascular endothelial growth factor (VEGF) is the principle driver of angiogenesis and the Notch receptor pathway for its control.

Non-sprouting or splitting angiogenesis is the development of a new vessel by the splitting of existing ones. This involves the formation of a core of pericytes and myofibroblasts between two vessels. These tissues form the extracellular matrix for growth of a new vessel lumen. The process is more economic than sprouting angiogenesis in the number of endothelial cells required, which is an advantage during embryonic development. It is important in the growth of capillary networks throughout life.

1.2 Closure of the Neural Tube and Development of the Head Arteries

In the embryonic period, massive changes in the distribution of newly formed vessels take place in a recognisable series of events. D. H. Padget divided the development of the cranial vessels into seven stages (see below) after which the adult configuration of arteries is established. The development of veins and dural sinuses takes longer and continues up to and beyond birth.

First we need to review the steps in the development of the head and in particular how the brain and facial structures appear.

1.2.1 Pre-choroidal Stage

Closure of the neural tube occurs at about 24 days after the start of the embryonic period. Blood vessels develop from a mesh of primitive cells (meninx primitiva) on its surface. Initially, arteries and veins are indistinguishable amongst these vessels, arranged as a network of vascular channels (Fig. 1.1). Longitudinal arterial channels develop ventral to the neural tube within the meninx primitiva. These comprise the longitudinal neural system (LNS). This process is preceded by the development of the heart and paired ventral and dorsal aortae from the truncus arteriosus.

Fig. 1.1

During the fourth week, the cranial neural tube develops three expansions termed primary brain vesicles. These are called prosencephalon (forebrain), mesencephalon (midbrain) and rhombencephalon (hindbrain). The ventricles form within these expansions.

1.2.2 Choroidal Stage

The increasing metabolic demand of the neural tube prompts invaginations of choroid from the meninx primitiva into ventricles within the vesicles so that blood supply occurs from both inner (ependymal) and outer (pial) surfaces.

During the fifth week, the primary vesicles develop secondary vesicles. These involve division of the prosencephalon into telencephalon and diencephalon and the rhombencephalon into metencephalon and myelencephalon. Thus, there are now five vesicles. At the same time, the branchial pouches are maturing.

1.2.3 Branchial Stage

The head develops around the rostral end of the neural tube with the face and neck forming ventral to the developing brain. These structures are derived from a series of branchial pouches with intervening arches (called pharyngeal arches in humans) and appear in the fourth week. They represent an evolutionary period when the organism depended on gills.

The head and neck structures are formed from the cranial three branchial arches and develop from neural crest cells together with contributions from paraxial mesoderm, ectoderm and endoderm.

The patterning information is provided by the cranial neural crest cells and can be traced to a transient period of hindbrain segmentation in seven subdivisions called rhombomeres. Each rhombomere has a unique identity provided by Hox gene expression. The gene products are Hox proteins (i.e. transcription factors) which dictate the ordered development of facial structures and the migration and differentiation of neural crest tissue into the first three branchial arches. They control the orientation of nerves, ganglia, bone, cartilage and connective tissue [1].

Paired connections between the ventral and dorsal aortae form between the pharyngeal arches. There are six arch arteries, separated by the transient pharyngeal pouches. The formation of the heart and great vessels is well described in general texts and will not be covered here. It should be understood that the six aortic arch arteries arising between the dorsal aorta and the ventral aortic sac are not present simultaneously. The three rostral arches concern us since the carotid arterial system develops from them. The posterior cerebral circulation develops as the meninx coalescences to form segmental and longitudinal arteries. The longitudinal intersegmental arteries form a system of vessels termed the longitudinal neural system (LNS) with the adult pattern emerging after the carotid system (Fig. 1.1).

1.2.4 Development of the Carotid and Vertebrobasilar System

This section will describe the stages in the development of the carotid artery. Our understanding of the cranial artery developments in the embryo comes from studies of post-mortem tissue. E. D. Congdon in 1922 [2] described the aortic arch system and the origins of the major cerebral arteries, i.e. carotid, vertebral and basilar. The details of how the cranial vasculature changes during the embryonic period were described by D. H. Padget [3] in astudy of 22 embryos held in the Carnegie Collection, Washington.

She identified the seven stages in this process and related these to the size of the embryos at each stage:

Stage 1 = 4–5 mm CRL
Stage 2 = 5–6 mm CRL
Stage 3 = 7–12 mm CRL
Stage 4 = 12–14 mm CRL
Stage 5 = 16–18 mm CRL
Stage 6 = 20–24 mm CRL
Stage 7 = 40 mm CRL

The internal carotid artery is established in the first three stages and the vertebrobasilar arteries by the fourth stage. These will be described chronologically. Other developments are easier to describe as systems because they develop in parallel streams.

1.2.4.1 Stage 1

Six aortic arch arteries connect the dorsal and ventral aorta, of which the upper three develop into the carotid system. The adult pattern results from a process of regression of various components of the three rostral connections (Fig.1.2a).

Fig. 1.2

Stage 1, development of carotid arteries. The three rostral aortic arches connect the ventral and dorsal aorta (a). Regressions result in the arrangement shown in (b).Interconnecting arteries between the first and second arches and with the longitudinal neural system (LNS) are now evident. In (c) parts of the first and second arch arteries have regressed and branches arising from the dorsal aorta rostral to the first arch artery developed. (Published with kind permission of © Henry Byrne, 2017. All rights reserved)

The dorsal aorta caudal to the third arch involutes and its rostral portion forms the first section of the primitive internal carotid artery. Its connection with the ventral aorta remains and the caudal portion of the ventral aorta becomes the common carotid artery. The ventral portions of the first and second arches and the dorsal part of the first arch also regress leaving an inter-connecting vessel between the first and second arches and the dorsal portion of the second arch (Fig. 1.2b, c).

The most rostral extent of the dorsal aorta, now the primitive internal carotid artery, divides into a ventral branch or anterior division which forms the anterior cerebral artery and a dorsal or posterior division which is the precursor of the posterior communicating artery. These vessels supply the developing prosencephalon (subsequently the telencephalon) and mesencephalon, respectively. The internal carotid artery (ICA) also supplies the rhombencephalon and the emerging LNS by the transient primitive trigeminal, otic and hypoglossal arteries (Fig. 1.3).

Fig. 1.3

Graphic reconstruction of cranial arteries in a 4 mm embryo by Padget [3]. Note the rostral division of the internal carotid arteries, the prominence of the branchial hyoid artery and the LNS emerging from a network of vessels and supplied from the internal carotid by trigeminal, otic and hypoglossal arteries (Reproduced with permission)

The dorsal aorta gives three branches rostral to the first arch – the ventral ophthalmic artery (VOA), the dorsal ophthalmic artery (DOA) and most caudally the primitive maxillary artery. The primitive maxillary artery supplies Rathke’s pouch,¹ from which the anterior pituitary develops. It appears before the optic vesicle (Fig. 1.2c).

1.2.4.2 Stage 2

The internal carotid artery is thus formed from the dorsal aorta and the third arch artery with part of the ventral aorta. The second arch artery becomes the hyoid trunk but maintains a connection with the first arch. This connection with the first arch is destined to become the stapedial artery, whilst the remnant of the first arch artery becomes the mandibular artery.

At this time (about 6 mm CRL), paired ventral pharyngeal arteries develop from the third arch. The ventral pharyngeal artery is destined to form the proximal part of the external carotid artery but it maintains a connection with the second arch (marked * on Fig. 1.4). It will form the lingo-facial system with lingual and thyroid branches.

Fig. 1.4

Stage 2. The stapedial artery links the first and second arch arteries and the ventral pharyngeal artery develops from the third arch. ICA internal carotid artery, CCA common carotid artery (Published with kind permission of © Henry Byrne, 2012. All rights reserved)

The connection to the second arch provides a link to the hyoid/stapedial system and is the key to understanding the development of the internal maxillary artery (second arch) and the middle meningeal artery (first arch).

Also in this stage, we see initial signs of the two primitive ophthalmic arteries (VOA and DOA) as the eye starts to develop. These will eventually regress leaving a single ophthalmic artery that follows the course of the VOA, whilst the DOA regresses and forms the precursor of the inferolateral trunk (ILT). The last of these three rostral branches of the dorsal aorta is the primitive maxillary artery, which is destined to survive in the adult pattern as the posteroinferior hypophyseal artery (PIHA).

Finally, because the posterior division of the internal carotid artery, i.e. the posterior communicating artery, consolidates its connection to the LNS, the primitive trigeminal, otic and hypoglossal arteries regress.

1.2.4.3 Stages 3 and 4

These stages encompass the transition from the branchial to post-branchial stages. The cranial divisions of the internal carotid artery (i.e. ventral and dorsal branches) develop. The ventral division forms the primitive olfactory artery from which the VOA arises. It also gives the anterior choroidal artery and small branches, which will coalesce into the middle cerebral artery as the telencephalon grows. The dorsal or posterior division forms the posterior communicating artery, which gives the posterior choroidal artery and supplies the mesencephalon and emerging basilar artery. The paired posterior choroidal arteries supply the diencephalon together with the anterior choroidal arteries.

The formation of the internal maxillary artery and middle meningeal artery is complex. This is because of the development of the face after completion of the branchial stage causes arteries (and arterial territories) to establish and then partially or completely regress as new patterns of blood supply develop. At the beginning of the fourth stage, the stapedial artery is formed as the continuation of the second arch’s hyoid artery trunk and an arterial link to the first arch. It divides into dorsal or supraorbital and ventral maxillomandibular divisions. The supraorbital branch is taken over by the ophthalmic system and the maxillomandibular trunk annexed by the developing internal maxillary artery (Fig. 1.5). These processes will be described in more detail below.

Fig. 1.5

Stage 3: Regression of the stapedial artery and annexation of its territory by the ventral pharyngeal system. MMA middle meningeal artery, IMA internal maxillary artery. See Figs. 1.2 and 1.4 for other abbreviations (Published with kind permission of © Henry Byrne, 2017. All rights reserved)

The basilar artery is formed by fusion of the parallel LNS on the midline surface of the developing hindbrain. Initially its caudal supply is from the first segmental artery of the aorta and the primitive hypoglossal artery. At this stage, lateral to the LNS and the developing basilar artery longitudinal channels are prominent. These transient arteries are called the primitive lateral vertebrobasilar anastomoses. They regress as the more medial basilar and vertebral arteries mature. The vertebral arteries are formed from longitudinal channels between the upper six spinal segments. Other connections between these segments and the aorta regress as the vertebral arteries grow. With growth of the hindbrain vesicles, symmetrical branches of the basilar artery appear.

1.2.5 Embryological Basis of Variations in the Carotid Artery

Before considering potential arterial anomalies, it is worth revisiting the primitive pattern in which the dorsal aorta and LNS develop from segmental centres. The LNS supplies the developing hindbrain comprising the mesencephalon, metencephalon and myelencephalon secondary vesicles and the primitive carotid artery the forebrain comprising the telencephalon and diencephalon secondary vesicles (Fig. 1.6).

Fig. 1.6

Development of secondary brain vesicles (5 weeks). The arterial supply to the secondary vesicles are numbered; 1 anterior division of ICA, 2 anterior cerebral artery (from which the middle cerebral artery arises – dotted line), 3 anterior choroidal artery, 4 posterior communicating artery, 5 posterior choroidal arteries, 6 collicular arteries, 7 superior cerebellar artery, 8 anterior inferior cerebellar artery, 9 posterior inferior cerebellar artery, 10 proatlantal artery, 11 primitive trigeminal artery (Published with kind permission of © Henry Byrne, 2012. All rights reserved)

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